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Paediatric or syndromic cardiomyopathy v7.2 MT-TL1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TL1.
Paediatric or syndromic cardiomyopathy v7.2 MT-TL1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, the rating should remain amber on this panel.

This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.; to: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

This gene can therefore be promoted to green rating on the next GMS update.
Paediatric or syndromic cardiomyopathy v7.2 MT-TL1 Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Changed rating: GREEN
Paediatric or syndromic cardiomyopathy v7.2 MT-TL1 Achchuthan Shanmugasundram Entity copied from Hypertrophic cardiomyopathy v5.6
Paediatric or syndromic cardiomyopathy v7.2 MT-TL1 Achchuthan Shanmugasundram gene: MT-TL1 was added
gene: MT-TL1 was added to Paediatric or syndromic cardiomyopathy. Sources: South West GLH,Expert Review,Expert Review Amber
locus-type-rna-transfer tags were added to gene: MT-TL1.
Mode of inheritance for gene gene: MT-TL1 was set to MITOCHONDRIAL
Publications for gene: MT-TL1 were set to 7473662; 8477849; 12874464; 14673589; 25639022; 30888501; 30133155
Phenotypes for gene: MT-TL1 were set to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; hypertrophic cardiomyopathy, MONDO:0005045
Hypertrophic cardiomyopathy v5.6 MT-TL1 Achchuthan Shanmugasundram Phenotypes for gene: MT-TL1 were changed from to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; hypertrophic cardiomyopathy, MONDO:0005045
Hypertrophic cardiomyopathy v5.5 MT-TL1 Achchuthan Shanmugasundram Publications for gene: MT-TL1 were set to
Hypertrophic cardiomyopathy v5.4 MT-TL1 Achchuthan Shanmugasundram Classified gene: MT-TL1 as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v5.4 MT-TL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, Hypertrophic cardiomyopathy is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

However, it should be noted that R131 is only intended for genes associated with isolated HCM and not for syndromic genes. So, the rating should remain amber on this panel.

This gene is therefore better placed as a green rated gene on the WGS clinical indication R135 Paediatric or syndromic cardiomyopathy.
Hypertrophic cardiomyopathy v5.4 MT-TL1 Achchuthan Shanmugasundram Gene: mt-tl1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.6 MT-TL1 Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TL1.
Hypertrophic cardiomyopathy v5.3 MT-TL1 Achchuthan Shanmugasundram changed review comment from: PMID:7473662 - The m.3243 A > G variant segregated with maternally inherited diabetes mellitus, sensorineural deafness, hypertrophic cardiomyopathy (HCM), or renal failure in a large pedigree of 35 affected members across four generations.

PMID:8477849 - The m.3243 A > G variant was identified in a family suffering from a syndrome with diabetes, deafness and HCMN as main clinical features.

PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had HCM as one of the clinical manifestations.

PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and HCM.

PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with HCM among several clinical manifestations.

PMID:30888501 - Retrospectively reviewed 27 MELAS patients from a patient cohort seen at a hospital, of which 13 patients were diagnosed with m.3243 A > G variant. HCM was found in one of them, while wolff parkinson white and congestive heart failure were reported in one each.

PMID:30133155 - Nine unrelated patients were reported with m.3243 A > G variant, of which only three patients met the criteria for MELAS syndrome. HCM was reported in eight of these patients moderate to severe regurgitation of various valves. Electrocardiography (ECG) showed preexcitation pattern with short PR intervals and delta waves (Wolff‐Parkinson‐White) in three patients and sick sinus syndrome plus atrioventricular block I in one patient. ; to: As per https://www.mitophen.org, there are more than ten different patients reported in peer-reviewed scientific literature with m.3243A>G variant and with hypertrophic cardiomyopathy (HCM) as one of the presenting phenotypes

PMID:7473662 - The m.3243 A > G variant segregated with maternally inherited diabetes mellitus, sensorineural deafness, HCM, or renal failure in a large pedigree of 35 affected members across four generations.

PMID:8477849 - The m.3243 A > G variant was identified in a family suffering from a syndrome with diabetes, deafness and HCMN as main clinical features.

PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had HCM as one of the clinical manifestations.

PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and HCM.

PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with HCM among several clinical manifestations.

PMID:30888501 - Retrospectively reviewed 27 MELAS patients from a patient cohort seen at a hospital, of which 13 patients were diagnosed with m.3243 A > G variant. HCM was found in one of them, while wolff parkinson white and congestive heart failure were reported in one each.

PMID:30133155 - Nine unrelated patients were reported with m.3243 A > G variant, of which only three patients met the criteria for MELAS syndrome. HCM was reported in eight of these patients moderate to severe regurgitation of various valves. Electrocardiography (ECG) showed preexcitation pattern with short PR intervals and delta waves (Wolff‐Parkinson‐White) in three patients and sick sinus syndrome plus atrioventricular block I in one patient.
Hypertrophic cardiomyopathy v5.3 MT-TL1 Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Changed publications to: 7473662, 8477849, 12874464, 14673589, 25639022, 30888501, 30133155; Changed phenotypes to: MELAS syndrome caused by mutation in MTTL1, MONDO:0800032, hypertrophic cardiomyopathy, MONDO:0005045
Hypertrophic cardiomyopathy v5.3 MT-TL1 Achchuthan Shanmugasundram changed review comment from: PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had hypertrophic cardiomyopathy (HCM) as one of the clinical manifestations.

PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and HCM.

PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with HCM among several clinical manifestations.

PMID:30888501 - Retrospectively reviewed 27 MELAS patients from a patient cohort seen at a hospital, of which 13 patients were diagnosed with m.3243 A > G variant. HCM was found in one of them, while wolff parkinson white and congestive heart failure were reported in one each.; to: PMID:7473662 - The m.3243 A > G variant segregated with maternally inherited diabetes mellitus, sensorineural deafness, hypertrophic cardiomyopathy (HCM), or renal failure in a large pedigree of 35 affected members across four generations.

PMID:8477849 - The m.3243 A > G variant was identified in a family suffering from a syndrome with diabetes, deafness and HCMN as main clinical features.

PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had HCM as one of the clinical manifestations.

PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and HCM.

PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with HCM among several clinical manifestations.

PMID:30888501 - Retrospectively reviewed 27 MELAS patients from a patient cohort seen at a hospital, of which 13 patients were diagnosed with m.3243 A > G variant. HCM was found in one of them, while wolff parkinson white and congestive heart failure were reported in one each.

PMID:30133155 - Nine unrelated patients were reported with m.3243 A > G variant, of which only three patients met the criteria for MELAS syndrome. HCM was reported in eight of these patients moderate to severe regurgitation of various valves. Electrocardiography (ECG) showed preexcitation pattern with short PR intervals and delta waves (Wolff‐Parkinson‐White) in three patients and sick sinus syndrome plus atrioventricular block I in one patient.
Hypertrophic cardiomyopathy v5.3 MT-TL1 Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Changed publications to: 7473662, 12874464, 14673589, 25639022, 30888501
Hypertrophic cardiomyopathy v5.3 MT-TL1 Achchuthan Shanmugasundram changed review comment from: PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had hypertrophic cardiomyopathy as one of the clinical manifestations.

PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and hypertrophic cardiomyopathy.

PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with hypertrophic cardiomyopathy among several clinical manifestations.; to: PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had hypertrophic cardiomyopathy (HCM) as one of the clinical manifestations.

PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and HCM.

PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with HCM among several clinical manifestations.

PMID:30888501 - Retrospectively reviewed 27 MELAS patients from a patient cohort seen at a hospital, of which 13 patients were diagnosed with m.3243 A > G variant. HCM was found in one of them, while wolff parkinson white and congestive heart failure were reported in one each.
Hypertrophic cardiomyopathy v5.3 MT-TL1 Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Changed publications to: 12874464, 14673589, 25639022, 30888501
Hypertrophic cardiomyopathy v5.3 MT-TL1 Achchuthan Shanmugasundram reviewed gene: MT-TL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 12874464, 14673589, 25639022; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.6 MT-TL1 Achchuthan Shanmugasundram Classified gene: MT-TL1 as Amber List (moderate evidence)
Optic neuropathy v5.6 MT-TL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of m.3243 A > G heteroplasmic variant from MT-TL1 with optic neuropathy/ optic atrophy. Hence, this gene can be promoted to green rating in the next GMS update.
Optic neuropathy v5.6 MT-TL1 Achchuthan Shanmugasundram Gene: mt-tl1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.5 MT-TL1 Achchuthan Shanmugasundram Phenotypes for gene: MT-TL1 were changed from to MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; optic atrophy, MONDO:0003608
Optic neuropathy v5.4 MT-TL1 Achchuthan Shanmugasundram Publications for gene: MT-TL1 were set to
Optic neuropathy v5.3 MT-TL1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MT-TL1.
Tag Q2_25_expert_review tag was added to gene: MT-TL1.
Tag Q2_25_ NHS_review tag was added to gene: MT-TL1.
Optic neuropathy v5.3 MT-TL1 Achchuthan Shanmugasundram edited their review of gene: MT-TL1: Added comment: As per https://www.mitophen.org, there are seven different patients reported in peer-reviewed scientific literature with m.3243A>G variant and with optic atrophy as one of the presenting phenotypes. Two additional patients were reported with optic disc pallor as one of the phenotypes.

PMID:7599199 - 14 patients with heteroplasmic m.3243A>G variant, of which only six patients had seizures and recurrent strokes, the core clinical features of the MELAS phenotype. One of them presented with optic atrophy.

PMID:7600089 - 22 probands with heteroplasmic m.3243A>G variant, of which 10 had clinical features consistent with MELAS syndrome. One had optic atrophy.

PMID:8363452 - A 15-year-old boy was reported with heteroplasmic m.3243A>G variant and with bilateral optic atrophy since 8 years of age.

PMID:8676159 - An 18-year-old male patient was reported with myoclonic epilepsy with ragged red fibres (MERRF) syndrome and with heteroplasmic m.3243A>G variant. The patient had bialateral optic atrophy.

PMID:9228247 - Two patients with MELAS syndrome and m.3243A>G variant were reported with optic neuropathy.

PMID:9619647 - A 21 year-old male patient with overlapping MELAS (mitochondrial encephalomyopathy, lactic acidosis, and 'stroke-like' episodes) and Kearns-Sayre syndrome. The heteroplasmic m.3243A>G variant has been identified in muscle tissue (79%), fibroblasts (49%) and blood cells (37%). There was no variant identified in E1alpha gene. Optic atrophy reported.

PMID:22249460 - The m.3243A>G variant was identified in half of 14 patients reported in this study, of which optic atrophy was present in two.

PMID:37095452 - Ischemic optic neuropathy reported as the first presentation in a patient with m.3243 A > G variant responsible for MELAS syndrome.; Changed publications to: 7599199, 7600089, 8363452, 8676159, 9228247, 9619647, 22249460, 37095452
Optic neuropathy v5.3 MT-TL1 Achchuthan Shanmugasundram reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: MELAS syndrome caused by mutation in MTTL1, MONDO:0800032, optic atrophy, MONDO:0003608; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.10 MT-TP Katherine Schon reviewed gene: MT-TP: Rating: AMBER; Mode of pathogenicity: Other; Publications: 7689388, 32305257; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.10 MT-TE Katherine Schon reviewed gene: MT-TE: Rating: GREEN; Mode of pathogenicity: Other; Publications: 7726155, 21931168, 33128823, 15607216; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.10 MT-TL1 Katherine Schon reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 23355809, 20458543, 33484420; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.10 MT-TG Katherine Schon reviewed gene: MT-TG: Rating: GREEN; Mode of pathogenicity: Other; Publications: 16120360, 11971101; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.10 MT-TK Katherine Schon reviewed gene: MT-TK: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.10 MT-TN Katherine Schon reviewed gene: MT-TN: Rating: GREEN; Mode of pathogenicity: Other; Publications: 23696415, 31026515, 8254046; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.10 MT-TA Katherine Schon reviewed gene: MT-TA: Rating: AMBER; Mode of pathogenicity: Other; Publications: 17825557; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.10 MT-TW Katherine Schon reviewed gene: MT-TW: Rating: GREEN; Mode of pathogenicity: Other; Publications: 9673981, 23841600; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Congenital myopathy v6.9 MT-TP Achchuthan Shanmugasundram gene: MT-TP was added
gene: MT-TP was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene gene: MT-TP was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TP was set to Other
Congenital myopathy v6.9 MT-TE Achchuthan Shanmugasundram gene: MT-TE was added
gene: MT-TE was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene gene: MT-TE was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TE was set to Other
Congenital myopathy v6.9 MT-TG Achchuthan Shanmugasundram gene: MT-TG was added
gene: MT-TG was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene gene: MT-TG was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TG was set to Other
Congenital myopathy v6.9 MT-TK Achchuthan Shanmugasundram gene: MT-TK was added
gene: MT-TK was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TK was set to Other
Congenital myopathy v6.9 MT-TN Achchuthan Shanmugasundram gene: MT-TN was added
gene: MT-TN was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene gene: MT-TN was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TN was set to Other
Congenital myopathy v6.9 MT-TA Achchuthan Shanmugasundram gene: MT-TA was added
gene: MT-TA was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene gene: MT-TA was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TA was set to Other
Congenital myopathy v6.9 MT-TW Achchuthan Shanmugasundram gene: MT-TW was added
gene: MT-TW was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene gene: MT-TW was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TW was set to Other
Monogenic hearing loss v5.10 MT-TS2 Katherine Schon reviewed gene: MT-TS2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 10090882; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Monogenic hearing loss v5.10 MT-TK Katherine Schon reviewed gene: MT-TK: Rating: GREEN; Mode of pathogenicity: Other; Publications: https://www.ncbi.nlm.nih.gov/books/NBK1520/ (further reference from Table 2), 8651277; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Monogenic hearing loss v5.10 MT-CO1 Katherine Schon reviewed gene: MT-CO1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29605341, 36524552; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Monogenic hearing loss v5.10 MT-TL1 Katherine Schon reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 22403016, 35455034, 23355809; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Monogenic hearing loss v5.9 MT-TS2 Achchuthan Shanmugasundram gene: MT-TS2 was added
gene: MT-TS2 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene gene: MT-TS2 was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TS2 was set to Other
Monogenic hearing loss v5.9 MT-TK Achchuthan Shanmugasundram gene: MT-TK was added
gene: MT-TK was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TK was set to Other
Hypertrophic cardiomyopathy v5.3 MT-ND5 Katherine Schon reviewed gene: MT-ND5: Rating: GREEN; Mode of pathogenicity: ; Publications: 22759514, 30587702; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Hypertrophic cardiomyopathy v5.3 MT-TL1 Katherine Schon reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 22513320, 31403078, 23355809; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Hypertrophic cardiomyopathy v5.3 MT-TV Katherine Schon reviewed gene: MT-TV: Rating: GREEN; Mode of pathogenicity: Other; Publications: 34298071, 15320572; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Hypertrophic cardiomyopathy v5.2 MT-ND5 Achchuthan Shanmugasundram gene: MT-ND5 was added
gene: MT-ND5 was added to Hypertrophic cardiomyopathy. Sources: Literature
Mode of inheritance for gene gene: MT-ND5 was set to MITOCHONDRIAL
Hypertrophic cardiomyopathy v5.2 MT-TV Achchuthan Shanmugasundram gene: MT-TV was added
gene: MT-TV was added to Hypertrophic cardiomyopathy. Sources: Literature
Mode of inheritance for gene gene: MT-TV was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TV was set to Other
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.5 STX16 Achchuthan Shanmugasundram Phenotypes for gene: STX16 were changed from Pseudohypoparathyroidism, type IB OMIM:603233; pseudohypoparathyroidism type 1B:MONDO:0011301 to Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.4 STX16 Achchuthan Shanmugasundram Classified gene: STX16 as Amber List (moderate evidence)
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.4 STX16 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of STX16 deletions with Pseudohypoparathyroidism Ib (MIM #603233). As reviewed by Treena Cranston on Familial hypoparathyroidism panel (please see her review below, which was copied from that panel), the pseudohypoparathyroidism phenotype should be covered by this panel (R293) rather than R153. Hence, this gene should be considered for promotion to green rating on this panel in the next GMS update.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.4 STX16 Achchuthan Shanmugasundram Gene: stx16 has been classified as Amber List (Moderate Evidence).
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.3 STX16 Achchuthan Shanmugasundram edited their review of gene: STX16: Changed rating: GREEN; Changed phenotypes to: Pseudohypoparathyroidism Ib, OMIM:603233; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.3 STX16 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: STX16 is not clearly an imprinted gene. As reported in publications, only maternally inherited deletions are associated with this phenotype. Deletions in this gene are thought to disrupt cis-acting regulation of GNAS expression.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.3 STX16 Achchuthan Shanmugasundram Mode of inheritance for gene: STX16 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.2 STX16 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: STX16.
Tag Q2_25_expert_review tag was added to gene: STX16.
Severe early-onset obesity v5.18 STX16 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: STX16 is not clearly an imprinted gene. As reported in publications, only maternally inherited deletions are associated with this phenotype. Deletions in this gene are thought to disrupt cis-acting regulation of GNAS expression.
Severe early-onset obesity v5.18 STX16 Achchuthan Shanmugasundram Mode of inheritance for gene: STX16 was changed from MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe early-onset obesity v5.17 STX16 Achchuthan Shanmugasundram edited their review of gene: STX16: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe early-onset obesity v5.17 STX16 Achchuthan Shanmugasundram Mode of inheritance for gene: STX16 was changed from MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Severe early-onset obesity v5.16 STX16 Achchuthan Shanmugasundram edited their review of gene: STX16: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.2 STX16 Achchuthan Shanmugasundram Entity copied from Familial hypoparathyroidism v3.1
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.2 STX16 Achchuthan Shanmugasundram gene: STX16 was added
gene: STX16 was added to Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis. Sources: NHS GMS,Expert Review Amber,Literature
non-coding-known-pathogenic, cnv tags were added to gene: STX16.
Mode of inheritance for gene: STX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STX16 were set to 14561710; 15579741; 15800843; 33320452; 32337648; 35119251
Phenotypes for gene: STX16 were set to Pseudohypoparathyroidism, type IB OMIM:603233; pseudohypoparathyroidism type 1B:MONDO:0011301
Severe early-onset obesity v5.16 STX16 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: STX16.
Severe early-onset obesity v5.16 STX16 Achchuthan Shanmugasundram changed review comment from: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion.

PMID:28453643 reported five patients reported with obesity with onset ranging from 3-12 months of age. Deletion of STX16 gene (either 3-kb or 4.4-kb) was reported in these cases confirming genetic diagnosis of Pseudohypoparathyroidism, type IB. All these patients inherited STX16 deletions from their unaffected mothers, and these deletions reside on paternal allele of these mothers. This indicates that maternally inherited deletions are associated with the phenotype. Excessive weight gain preceded other clinical or laboratory signs of PHP1B by more than a decade in some patients. One of these patients had symptomatic hypocalcemia and elevated PTH levels when admitted to hospital at 11.5 years, and another was reported with asymptomatic hypocalcemia and an elevated PTH level only after establishing the genetic defect.

As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years and in the absence of significant features.

All the cases reported above had early onset obesity before the age of 5 and appears severe. However, the patient from PMID:27338644 had other presentations such as macrosomia and macrocephaly suggesting the phenotype is syndromic. Although some of the cases reported in PMID:28453643 had hypocalcemia and an elevated PTH level, their onset was much later than that of obesity. Hence, it is useful to include this gene on this panel to get diagnosis for patients early in their life and before the onset of PHP1B. Clinical opinion is therefore sought in relation to promoting this gene to green rating on this panel.; to: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion.

PMID:28453643 reported five patients reported with obesity with onset ranging from 3-12 months of age. Deletion of STX16 gene (either 3-kb or 4.4-kb) was reported in these cases confirming genetic diagnosis of Pseudohypoparathyroidism, type IB. All these patients inherited STX16 deletions from their unaffected mothers, and these deletions reside on paternal allele of these mothers. This indicates that maternally inherited deletions are associated with the phenotype. Excessive weight gain preceded other clinical or laboratory signs of PHP1B by more than a decade in some patients. One of these patients had symptomatic hypocalcemia and elevated PTH levels when admitted to hospital at 11.5 years, and another was reported with asymptomatic hypocalcemia and an elevated PTH level only after establishing the genetic defect.

As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years and in the absence of significant features.

All the cases reported above had early onset obesity before the age of 5 and appears severe. However, the patient from PMID:27338644 had other presentations such as macrosomia and macrocephaly suggesting the phenotype is syndromic. Although some of the cases reported in PMID:28453643 had hypocalcemia and an elevated PTH level, their onset was much later than that of obesity. Hence, it is useful to include this gene on this panel to get diagnosis for patients early in their life and before the onset of PHP1B.
Cholestasis v3.7 RINT1 Achchuthan Shanmugasundram Tag Q2_25_ demote_amber was removed from gene: RINT1.
Tag Q2_25_ demote_red tag was added to gene: RINT1.
Cholestasis v3.7 RINT1 Achchuthan Shanmugasundram Tag Q2_25_ demote_red was removed from gene: RINT1.
Tag Q2_25_ demote_amber tag was added to gene: RINT1.
Cholestasis v3.7 RINT1 Achchuthan Shanmugasundram Tag Q2_25_ demote_red tag was added to gene: RINT1.
Tag Q2_25_expert_review tag was added to gene: RINT1.
Cholestasis v3.7 RINT1 Achchuthan Shanmugasundram changed review comment from: As reviewed previously, PMID:31204009 reported three unrelated individuals with compound heterozygous RINT1 variants and infantile acute liver failure (MIM #618641). However, focal cholestasis was only reported in one patient (proband 3), while jaundice was reported in a different patient (proband 1). Increased bilirubin levels are reported in all three patients. There is also functional evidence on patient dermal fibroblasts available for the splice-variant that was identified in all three patients.

PMID:37463447 reported three individuals from two unrelated families with novel biallelic RINT1 loss-of-function variants and they presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, dysmorphic features and neurodevelopmental delay, expanding the phenotypic spectrum of the disorder. Although acute liver failure or episodic liver dysfunction are reported in these cases, cholestasis or hyperbilirubinaemia are not reported.

PMID:39186236 also reported a patient withy acute liver failure due to RINT1 deficiency, however without any reports of cholestasis or hyperbilirubinaemia.

As per the National Genomic Test Directory (https://www.england.nhs.uk/publication/national-genomic-test-directories/), this panel includes both cholestasis and hyperbilirubinaemia.

As Zornitza Stark has reviewed this gene red on this panel based on the phenotype being acute liver failure, clinical opinion is sought on whether this gene can remain green on this panel.; to: As reviewed previously, PMID:31204009 reported three unrelated individuals with compound heterozygous RINT1 variants and infantile acute liver failure (MIM #618641). However, focal cholestasis was only reported in one patient (proband 3), while jaundice was reported in a different patient (proband 1). Increased bilirubin levels are reported in all three patients. There is also functional evidence on patient dermal fibroblasts available for the splice-variant that was identified in all three patients.

PMID:37463447 reported three individuals from two unrelated families with novel biallelic RINT1 loss-of-function variants and they presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, dysmorphic features and neurodevelopmental delay, expanding the phenotypic spectrum of the disorder. Although acute liver failure or episodic liver dysfunction are reported in these cases, cholestasis or hyperbilirubinaemia are not reported.

PMID:39186236 also reported a patient withy acute liver failure due to RINT1 deficiency, however without any reports of cholestasis or hyperbilirubinaemia.

As per the National Genomic Test Directory (https://www.england.nhs.uk/publication/national-genomic-test-directories/), this panel includes neonatal conjugated hyperbilirubinaemia, unexplained cholestasis or cholestasis of pregnancy-onset.

As Zornitza Stark has reviewed this gene red on this panel based on the phenotype being acute liver failure, clinical opinion is sought on whether this gene can remain green on this panel.
Cholestasis v3.7 RINT1 Achchuthan Shanmugasundram changed review comment from: As reviewed previously, PMID:31204009 reported three unrelated individuals with compound heterozygous RNT1 variants and infantile acute liver failure (MIM #618641). However, focal cholestasis was only reported in one patient (proband 3), while jaundice was reported in a different patient (proband 1). Increased bilirubin levels are reported in all three patients. There is also functional evidence on patient dermal fibroblasts available for the splice-variant that was identified in all three patients.

PMID:37463447 reported three individuals from two unrelated families with novel biallelic RINT1 loss-of-function variants and they presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, dysmorphic features and neurodevelopmental delay, expanding the phenotypic spectrum of the disorder. Although acute liver failure or episodic liver dysfunction are reported in these cases, cholestasis or hyperbilirubinaemia are not reported.

PMID:39186236 also reported a patient withy acute liver failure due to RINT1 deficiency, however without any reports of cholestasis or hyperbilirubinaemia.

As per the National Genomic Test Directory (https://www.england.nhs.uk/publication/national-genomic-test-directories/), this panel should include both cholestasis and hyperbilirubinaemia.

As Zornitza Stark has reviewed this gene red on this panel based on the phenotype being acute liver failure, clinical opinion is sought on whether this gene can remain green on this panel.; to: As reviewed previously, PMID:31204009 reported three unrelated individuals with compound heterozygous RINT1 variants and infantile acute liver failure (MIM #618641). However, focal cholestasis was only reported in one patient (proband 3), while jaundice was reported in a different patient (proband 1). Increased bilirubin levels are reported in all three patients. There is also functional evidence on patient dermal fibroblasts available for the splice-variant that was identified in all three patients.

PMID:37463447 reported three individuals from two unrelated families with novel biallelic RINT1 loss-of-function variants and they presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, dysmorphic features and neurodevelopmental delay, expanding the phenotypic spectrum of the disorder. Although acute liver failure or episodic liver dysfunction are reported in these cases, cholestasis or hyperbilirubinaemia are not reported.

PMID:39186236 also reported a patient withy acute liver failure due to RINT1 deficiency, however without any reports of cholestasis or hyperbilirubinaemia.

As per the National Genomic Test Directory (https://www.england.nhs.uk/publication/national-genomic-test-directories/), this panel includes both cholestasis and hyperbilirubinaemia.

As Zornitza Stark has reviewed this gene red on this panel based on the phenotype being acute liver failure, clinical opinion is sought on whether this gene can remain green on this panel.
Multi locus imprinting disorders v1.14 OOEP Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene is rated red on this panel after seeking clinical opinion from Helen Brittain.

This is a maternal effect gene with similar genotypes causing different phenotypes.

In PMID:29574422, a homozygous variant in mother resulted in a phenotype suggestive of MLID in the offspring, who was heterozygous for the same variant. The current standard testing for this type of finding appears to be MLID methylation test in the proband. In addition, this family is from South East Asian descent and this ethnicity is under-represented in population cohorts raising the question whether the variant might not be responsible for the clinical presentation.

In PMID:35946397, compound heterozygous variants (one of these variants is the same as the homozygous variant above) resulted in recurrent preimplantation embryonic arrest in the patient, which is a different phenotype from the one above. In addition, this phenotype does not clearly lead to inclusion in any current panels within the Genomic Medicine Service.; to: Comment on list classification: This gene is rated red on this panel after seeking clinical opinion from Helen Brittain.

This is a maternal effect gene with similar genotypes causing different phenotypes.

In PMID:29574422, a homozygous variant in mother resulted in a phenotype suggestive of MLID in the offspring, who was heterozygous for the same variant. The current standard testing for this type of finding appears to be MLID methylation test in the proband. In addition, this family is from South East Asian descent and this ethnicity is under-represented in population cohorts raising the question whether the variant might not be responsible for the clinical presentation.

In PMID:35946397, compound heterozygous variants (one of these variants is the same as the homozygous variant above) resulted in recurrent preimplantation embryonic arrest in the patient, which is a different phenotype from the one above. In addition, this phenotype does not clearly lead to inclusion in any current panels within the Genomic Medicine Service.
Multi locus imprinting disorders v1.14 OOEP Achchuthan Shanmugasundram Classified gene: OOEP as Red List (low evidence)
Multi locus imprinting disorders v1.14 OOEP Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene is rated red on this panel after seeking clinical opinion from Helen Brittain.

This is a maternal effect gene with similar genotypes causing different phenotypes.

In PMID:29574422, a homozygous variant in mother resulted in a phenotype suggestive of MLID in the offspring, who was heterozygous for the same variant. The current standard testing for this type of finding appears to be MLID methylation test in the proband. In addition, this family is from South East Asian descent and this ethnicity is under-represented in population cohorts raising the question whether the variant might not be responsible for the clinical presentation.

In PMID:35946397, compound heterozygous variants (one of these variants is the same as the homozygous variant above) resulted in recurrent preimplantation embryonic arrest in the patient, which is a different phenotype from the one above. In addition, this phenotype does not clearly lead to inclusion in any current panels within the Genomic Medicine Service.
Multi locus imprinting disorders v1.14 OOEP Achchuthan Shanmugasundram Gene: ooep has been classified as Red List (Low Evidence).
Multi locus imprinting disorders v1.13 OOEP Achchuthan Shanmugasundram Deleted their comment
Multi locus imprinting disorders v1.13 OOEP Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This is a maternal effect gene with similar genotypes causing different phenotypes. The homozygous variant in mother caused MLID in the offspring (PMID:29574422), and compound heterozygous variants (one of these variants is the same as the homozygous variant) caused recurrent preimplantation embryonic arrest. Hence, clinical opinion is being sought on the rating for this gene.; to: Comment on list classification: This gene is rated red on this panel after seeking clinical opinion from Helen Brittain.

This is a maternal effect gene with similar genotypes causing different phenotypes.

In PMID:29574422, a homozygous variant in mother resulted in a phenotype suggestive of MLID in the offspring, who was heterozygous for the same variant. The current standard testing for this type of finding appears to be MLID methylation test in the proaband.

In PMID:35946397, compound heterozygous variants (one of these variants is the same as the homozygous variant above) caused recurrent preimplantation embryonic arrest in the patient, which is a different phenotype from the one above. In addition, Hence, clinical opinion is being sought on the rating for this gene.
Multi locus imprinting disorders v1.13 OOEP Achchuthan Shanmugasundram Classified gene: OOEP as Red List (low evidence)
Multi locus imprinting disorders v1.13 OOEP Achchuthan Shanmugasundram Gene: ooep has been classified as Red List (Low Evidence).
Multi locus imprinting disorders v1.12 OOEP Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases: one with homozygous, and another with compound heterozygous variants, where one of these is the same as the homozygous variant. There is also some functional evidence available. However, similar genotypes cause different phenotypes. Hence, seeking clinical opinion on this gene before making green. The 'watchlist' tag is therefore added to reflect this.; to: Comment on list classification: This is a maternal effect gene with similar genotypes causing different phenotypes. The homozygous variant in mother caused MLID in the offspring (PMID:29574422), and compound heterozygous variants (one of these variants is the same as the homozygous variant) caused recurrent preimplantation embryonic arrest. Hence, clinical opinion is being sought on the rating for this gene.
Multi locus imprinting disorders v1.12 OOEP Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases: one with homozygous, and another with compound heterozygous variants, where one of these is the same as the homozygous variant. There is also some functional evidence available. However, similar genotypes cause different phenotypes. Hence, seeking clinical opinion on this gene before making green. The 'watchlist' tag is therefore added to reflect this.; to: Comment on list classification: There are two unrelated cases: one with homozygous, and another with compound heterozygous variants, where one of these is the same as the homozygous variant. There is also some functional evidence available. However, similar genotypes cause different phenotypes. Hence, seeking clinical opinion on this gene before making green. The 'watchlist' tag is therefore added to reflect this.
Multi locus imprinting disorders v1.12 OOEP Achchuthan Shanmugasundram Tag watchlist was removed from gene: OOEP.
Optic neuropathy v5.3 MT-TK Katherine Schon reviewed gene: MT-TK: Rating: GREEN; Mode of pathogenicity: Other; Publications: 23635963, 33766967; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.3 MT-ND5 Katherine Schon reviewed gene: MT-ND5: Rating: GREEN; Mode of pathogenicity: ; Publications: 27164671, 12736867, 38357617; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.3 MT-ND3 Katherine Schon reviewed gene: MT-ND3: Rating: GREEN; Mode of pathogenicity: ; Publications: 30199507, 19458970; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.3 MT-TS2 Katherine Schon reviewed gene: MT-TS2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 9135384, 10090882, 8432539; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.3 MT-ND4L Katherine Schon reviewed gene: MT-ND4L: Rating: GREEN; Mode of pathogenicity: ; Publications: 29210930, 36381806; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.3 MT-TL1 Katherine Schon reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 9228247, 39423307, 37095452; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.3 MT-ND2 Katherine Schon reviewed gene: MT-ND2: Rating: GREEN; Mode of pathogenicity: ; Publications: 11479733, 21145289; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Optic neuropathy v5.2 MT-TK Achchuthan Shanmugasundram gene: MT-TK was added
gene: MT-TK was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TK was set to Other
Optic neuropathy v5.2 MT-ND5 Achchuthan Shanmugasundram gene: MT-ND5 was added
gene: MT-ND5 was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene gene: MT-ND5 was set to MITOCHONDRIAL
Optic neuropathy v5.2 MT-ND3 Achchuthan Shanmugasundram gene: MT-ND3 was added
gene: MT-ND3 was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene gene: MT-ND3 was set to MITOCHONDRIAL
Optic neuropathy v5.2 MT-TS2 Achchuthan Shanmugasundram gene: MT-TS2 was added
gene: MT-TS2 was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene gene: MT-TS2 was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TS2 was set to Other
Optic neuropathy v5.2 MT-ND4L Achchuthan Shanmugasundram gene: MT-ND4L was added
gene: MT-ND4L was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene gene: MT-ND4L was set to MITOCHONDRIAL
Optic neuropathy v5.2 MT-TL1 Achchuthan Shanmugasundram gene: MT-TL1 was added
gene: MT-TL1 was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene gene: MT-TL1 was set to MITOCHONDRIAL
Mode of pathogenicity for gene: MT-TL1 was set to Other
Optic neuropathy v5.2 MT-ND2 Achchuthan Shanmugasundram gene: MT-ND2 was added
gene: MT-ND2 was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene gene: MT-ND2 was set to MITOCHONDRIAL
Retinal disorders v8.6 TBC1D32 Achchuthan Shanmugasundram Classified gene: TBC1D32 as Amber List (moderate evidence)
Retinal disorders v8.6 TBC1D32 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases and functional studies) for the promotion of this gene to green rating on the retinal disorders panel in the next GMS update.
Retinal disorders v8.6 TBC1D32 Achchuthan Shanmugasundram Gene: tbc1d32 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.5 TBC1D32 Achchuthan Shanmugasundram gene: TBC1D32 was added
gene: TBC1D32 was added to Retinal disorders. Sources: Literature
dd_review, Q2_25_ promote_green tags were added to gene: TBC1D32.
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 37768732
Phenotypes for gene: TBC1D32 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: TBC1D32 was set to GREEN
Added comment: PMID:37768732 reported the identification of biallelic variants in TBC1D32 gene in four individuals from three unrelated families with retinitis pigmentosa. In addition, data from Xenopus in vivo approaches and human induced pluripotent stem cell-derived (iPSC-derived) retinal models also support the disease association.

This gene is not yet associated with any phenotypes in OMIM.
Sources: Literature
Early onset or syndromic epilepsy v8.5 CELF4 Achchuthan Shanmugasundram Classified gene: CELF4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.5 CELF4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (nine unrelated cases with seizures) for the promotion of this gene to green rating on this panel in the next GMS update.
Early onset or syndromic epilepsy v8.5 CELF4 Achchuthan Shanmugasundram Gene: celf4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.4 CELF4 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CELF4.
Intellectual disability v9.28 CELF4 Achchuthan Shanmugasundram Classified gene: CELF4 as Amber List (moderate evidence)
Intellectual disability v9.28 CELF4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (12 unrelated cases with GDD/ ID) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.28 CELF4 Achchuthan Shanmugasundram Gene: celf4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.27 CELF4 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CELF4.
Early onset or syndromic epilepsy v8.4 CELF4 Achchuthan Shanmugasundram gene: CELF4 was added
gene: CELF4 was added to Early onset or syndromic epilepsy. Sources: Literature
Q2_25_ promote_green tags were added to gene: CELF4.
Mode of inheritance for gene: CELF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF4 were set to 40108438
Phenotypes for gene: CELF4 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CELF4 was set to GREEN
Added comment: PMID:40108438 reported 15 patients with heterozygous missense or loss-of-function variants clustering in the N-terminal of the CELF4 gene. Most patients presented with neurodevelopmental disorders including global developmental delay (12 patients), intellectual disability (8, of which moderate in 2, mild in 3, and severity not defined in 3), seizures (9) and overweight/obesity (10) that began in childhood. Clinical features are similar to the reported celf4-mouse mutant phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v9.27 CELF4 Achchuthan Shanmugasundram gene: CELF4 was added
gene: CELF4 was added to Intellectual disability. Sources: Literature
Q2_25_ promote_green tags were added to gene: CELF4.
Mode of inheritance for gene: CELF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF4 were set to 40108438
Phenotypes for gene: CELF4 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CELF4 was set to GREEN
Added comment: PMID:40108438 reported 15 patients with heterozygous missense or loss-of-function variants clustering in the N-terminal of the CELF4 gene. Most patients presented with neurodevelopmental disorders including global developmental delay (12 patients), intellectual disability (8, of which moderate in 2, mild in 3, and severity not defined in 3), seizures (9) and overweight/obesity (10) that began in childhood. Clinical features are similar to the reported celf4-mouse mutant phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Multi locus imprinting disorders v1.12 ZFP57 Achchuthan Shanmugasundram Classified gene: ZFP57 as Amber List (moderate evidence)
Multi locus imprinting disorders v1.12 ZFP57 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Multi locus imprinting disorders v1.12 ZFP57 Achchuthan Shanmugasundram Gene: zfp57 has been classified as Amber List (Moderate Evidence).
Multi locus imprinting disorders v1.11 ZFP57 Achchuthan Shanmugasundram Phenotypes for gene: ZFP57 were changed from MLID to {Diabetes mellitus, transient neonatal 1}, OMIM:601410; Multi-locus imprinting disturbance (MLID)
Multi locus imprinting disorders v1.10 ZFP57 Achchuthan Shanmugasundram Publications for gene: ZFP57 were set to PMID: 39090763
Multi locus imprinting disorders v1.9 ZFP57 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: ZFP57.
Multi locus imprinting disorders v1.9 ZFP57 Achchuthan Shanmugasundram reviewed gene: ZFP57: Rating: GREEN; Mode of pathogenicity: None; Publications: 35296332, 39090763; Phenotypes: {Diabetes mellitus, transient neonatal 1}, OMIM:601410; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Multi locus imprinting disorders v1.9 OOEP Achchuthan Shanmugasundram Classified gene: OOEP as Amber List (moderate evidence)
Multi locus imprinting disorders v1.9 OOEP Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases: one with homozygous, and another with compound heterozygous variants, where one of these is the same as the homozygous variant. There is also some functional evidence available. However, similar genotypes cause different phenotypes. Hence, seeking clinical opinion on this gene before making green. The 'watchlist' tag is therefore added to reflect this.
Multi locus imprinting disorders v1.9 OOEP Achchuthan Shanmugasundram Gene: ooep has been classified as Amber List (Moderate Evidence).
Multi locus imprinting disorders v1.8 OOEP Achchuthan Shanmugasundram Tag watchlist tag was added to gene: OOEP.
Multi locus imprinting disorders v1.8 OOEP Achchuthan Shanmugasundram Phenotypes for gene: OOEP were changed from MLID to Multi-locus imprinting disturbance (MLID)
Multi locus imprinting disorders v1.7 OOEP Achchuthan Shanmugasundram Publications for gene: OOEP were set to PMID: 39090763
Multi locus imprinting disorders v1.6 OOEP Achchuthan Shanmugasundram reviewed gene: OOEP: Rating: AMBER; Mode of pathogenicity: None; Publications: 29574422, 35946397, 39090763; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v4.4 CFAP74 Arina Puzriakova Tag watchlist was removed from gene: CFAP74.
Respiratory ciliopathies including non-CF bronchiectasis v4.4 CFAP74 Arina Puzriakova Tag Q1_25_ expert_review tag was added to gene: CFAP74.
Respiratory ciliopathies including non-CF bronchiectasis v4.4 CFAP74 Arina Puzriakova commented on gene: CFAP74
Limb disorders v7.8 RPL26 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are five unrelated families reported with congenital anomalies (particularly radial ray anomalies) and monoallelic RPL26 variants. Hence, this gene can be promoted to green rating in the next GMSW update.; to: Comment on list classification: There are five unrelated families reported with congenital anomalies (particularly radial ray anomalies) and monoallelic RPL26 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Limb disorders v7.8 RPL26 Achchuthan Shanmugasundram Classified gene: RPL26 as Amber List (moderate evidence)
Limb disorders v7.8 RPL26 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated families reported with congenital anomalies (particularly radial ray anomalies) and monoallelic RPL26 variants. Hence, this gene can be promoted to green rating in the next GMSW update.
Limb disorders v7.8 RPL26 Achchuthan Shanmugasundram Gene: rpl26 has been classified as Amber List (Moderate Evidence).
Limb disorders v7.7 RPL26 Achchuthan Shanmugasundram Phenotypes for gene: RPL26 were changed from Radial Ray abnormality to ?Diamond-Blackfan anemia 11, OMIM:614900
Limb disorders v7.6 RPL26 Achchuthan Shanmugasundram Publications for gene: RPL26 were set to
Limb disorders v7.5 RPL26 Achchuthan Shanmugasundram Mode of inheritance for gene: RPL26 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb disorders v7.4 RPL26 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: RPL26.
Limb disorders v7.4 RPL26 Achchuthan Shanmugasundram reviewed gene: RPL26: Rating: GREEN; Mode of pathogenicity: None; Publications: 39268718; Phenotypes: ?Diamond-Blackfan anemia 11, OMIM:614900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v4.20 RPL26 Achchuthan Shanmugasundram Classified gene: RPL26 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v4.20 RPL26 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are five unrelated families reported with monoallelic RPL26 variants in total (PMIDs: 22431104 & 39268718), only two unrelated individuals have been reported with cytopenia. Hence, this gene can only be rated amber with current evidence.
Cytopenia - NOT Fanconi anaemia v4.20 RPL26 Achchuthan Shanmugasundram Gene: rpl26 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v4.19 RPL26 Achchuthan Shanmugasundram Phenotypes for gene: RPL26 were changed from ?Diamond-Blackfan anemia 11, 614900 to ?Diamond-Blackfan anemia 11, OMIM:614900
Cytopenia - NOT Fanconi anaemia v4.18 RPL26 Achchuthan Shanmugasundram Publications for gene: RPL26 were set to
Cytopenia - NOT Fanconi anaemia v4.17 RPL26 Achchuthan Shanmugasundram Mode of inheritance for gene: RPL26 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v4.16 RPL26 Achchuthan Shanmugasundram reviewed gene: RPL26: Rating: AMBER; Mode of pathogenicity: None; Publications: 39268718; Phenotypes: ?Diamond-Blackfan anemia 11, OMIM:614900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb disorders v7.4 RPL17 Achchuthan Shanmugasundram Classified gene: RPL17 as Red List (low evidence)
Limb disorders v7.4 RPL17 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is only one family reported with skeletal abnormalities, this gene can only be rated red on this panel with the current evidence.
Limb disorders v7.4 RPL17 Achchuthan Shanmugasundram Gene: rpl17 has been classified as Red List (Low Evidence).
Limb disorders v7.3 RPL17 Achchuthan Shanmugasundram Phenotypes for gene: RPL17 were changed from Diamond-Blackfan anemia to Diamond-Blackfan anemia, MONDO:0015253
Limb disorders v7.2 RPL17 Achchuthan Shanmugasundram edited their review of gene: RPL17: Changed rating: RED
Cytopenia - NOT Fanconi anaemia v4.16 RPL17 Achchuthan Shanmugasundram Classified gene: RPL17 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v4.16 RPL17 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are two unrelated pedigrees and functional evidence available in support of the association of this gene to phenotype. Hence, this can be promoted to green rating in the next GMS update.
Cytopenia - NOT Fanconi anaemia v4.16 RPL17 Achchuthan Shanmugasundram Gene: rpl17 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v4.15 RPL17 Achchuthan Shanmugasundram Phenotypes for gene: RPL17 were changed from Diamond-Blackfan anemia to Diamond-Blackfan anemia, MONDO:0015253
Cytopenia - NOT Fanconi anaemia v4.14 RPL17 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: RPL17.
Limb disorders v7.2 RPL17 Achchuthan Shanmugasundram Entity copied from Cytopenia - NOT Fanconi anaemia v4.14
Limb disorders v7.2 RPL17 Achchuthan Shanmugasundram gene: RPL17 was added
gene: RPL17 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: RPL17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL17 were set to 39088281
Phenotypes for gene: RPL17 were set to Diamond-Blackfan anemia
Penetrance for gene: RPL17 were set to Incomplete
Cytopenia - NOT Fanconi anaemia v4.14 RPL17 Achchuthan Shanmugasundram reviewed gene: RPL17: Rating: GREEN; Mode of pathogenicity: None; Publications: 39088281; Phenotypes: Diamond-Blackfan anemia, MONDO:0015253; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v4.14 CASP10 Achchuthan Shanmugasundram Classified gene: CASP10 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v4.14 CASP10 Achchuthan Shanmugasundram Added comment: Comment on list classification: Despite sufficient cases being reported with the phenotype, the presence of identified variants in healthy individuals, reduced segregation of variants with the disease, inconsistencies in the reported phenotypes across cases with the same variants, and normal FAS-mediated apoptosis with variants from affected individuals suggest that this gene should not be promoted to green rating.
Cytopenia - NOT Fanconi anaemia v4.14 CASP10 Achchuthan Shanmugasundram Gene: casp10 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v4.13 CASP10 Achchuthan Shanmugasundram Classified gene: CASP10 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v4.13 CASP10 Achchuthan Shanmugasundram Gene: casp10 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v4.12 CASP10 Achchuthan Shanmugasundram Publications for gene: CASP10 were set to
Cytopenia - NOT Fanconi anaemia v4.11 CASP10 Achchuthan Shanmugasundram Phenotypes for gene: CASP10 were changed from ALPS to Autoimmune lymphoproliferative syndrome, type II, OMIM:603909
Cytopenia - NOT Fanconi anaemia v4.10 CASP10 Achchuthan Shanmugasundram Mode of inheritance for gene: CASP10 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v4.9 CASP10 Achchuthan Shanmugasundram commented on gene: CASP10: PMID:34329798 - Two patients were identified with heterozygous p.Ile406Leu variant and one was identified with p.Cys401LeufsTer15 variant. The p.Ile406Leu variant did not segregate with the disease, while the family of the patient with p.Cys401LeufsTer15 variant was not studied. The p.Ile406Leu variant, which was previously reported in several cases was found at an allele frequency of 2% in healthy individuals in certain ethnicities from the 1000 genomes database. In addition, functional assays did not show any impairment in one of these patients and five previously reported patients in comparison to healthy donors. Although p.Cys401LeufsTer15 variant was classified as likely pathogenic, it is also proposed that it is not per se causative of disease as the variant is present at higher than expected allele frequency in healthy individuals. There is also significant differences in the clinical presentations with the patient with this variant in this publication and a previously reported patient within the same variant. Another previously reported variant, p.Tyr446Cys was also present at an allele frequency of 4% in healthy individuals from 1000 genomes database, and p.Val410Ile was discarded as disease-causing by the same authors.

PMID:38704374 aimed to assess the impact of CASP10 variants on ALPS pathogenesis. Using a large cohort dataset, the authors were able to confirm that the missense variants p.Val410Ile and p.Tyr446Cys, are present in the general population at a high frequency. Furthermore, these variants do not affect the CASP10 catalytic domain and no difference was observed in CASP10 protein expression or FAS-mediated apoptosis between healthy controls and subjects bearing these variants in both homozygous and heterozygous states. Two patient had the CASP10 variant p.Cys401LeufsTer15, which lies within QACQG catalytic site in the CASP10 catalytic domain. One of the two patients was homozygous for this variant, resulting in a lack of Caspase-10 RNA and protein. However, it was reported that FAS-mediated apoptosis was comparable to healthy controls in each of the tested cell lines suspected to have a role in ALPS. In the other patient, who was heterozygous p.Cys401LeufsTer15, the authors report that although the levels of CASP10 protein expression was reduced, there was normal FAS-mediated apoptosis compared to healthy controls. From these results, it was concluded that Caspase-10 is dispensable for FAS-mediated apoptosis and an undetectable CASP10 protein expression has no impact on lymphocyte apoptosis and on individuals’ clinical and laboratory phenotype. It is also commented that post-translational or epigenetic mechanisms may play a role and yet unidentified.
Cytopenia - NOT Fanconi anaemia v4.9 CASP10 Achchuthan Shanmugasundram reviewed gene: CASP10: Rating: AMBER; Mode of pathogenicity: None; Publications: 34329798, 38704374; Phenotypes: Autoimmune lymphoproliferative syndrome, type II, OMIM:603909; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.11 SRPK3 Arina Puzriakova Phenotypes for gene: SRPK3 were changed from to Slowly progressive myopathy, digenic
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.10 SRPK3 Arina Puzriakova Publications for gene: SRPK3 were set to 38429495
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.9 SRPK3 Arina Puzriakova Mode of inheritance for gene: SRPK3 was changed from Other to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.8 SRPK3 Arina Puzriakova Classified gene: SRPK3 as Red List (low evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.8 SRPK3 Arina Puzriakova Added comment: Comment on list classification: There is no evidence that monogenic variants in this gene cause myopathy. Digenic inheritance is not currently accommodated in tiering. The TTN gene is already included on this panel as Green meaning cases could still be picked up if a TTN variant is present. As this is digenic, this gene has been made Red and tagged 'digenic'.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.8 SRPK3 Arina Puzriakova Gene: srpk3 has been classified as Red List (Low Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7 SRPK3 Arina Puzriakova Tag digenic tag was added to gene: SRPK3.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7 SRPK3 Arina Puzriakova reviewed gene: SRPK3: Rating: ; Mode of pathogenicity: None; Publications: 16140986, 38429495, 39667923; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Congenital myopathy v6.8 SRPK3 Arina Puzriakova Classified gene: SRPK3 as Red List (low evidence)
Congenital myopathy v6.8 SRPK3 Arina Puzriakova Added comment: Comment on list classification: There is no evidence that monogenic variants in this gene cause myopathy. Digenic inheritance is not currently accommodated in tiering. The TTN gene is already included on this panel as Green meaning cases could still be picked up if a TTN variant is present. As this is digenic, this gene has been made Red and tagged 'digenic'.
Congenital myopathy v6.8 SRPK3 Arina Puzriakova Gene: srpk3 has been classified as Red List (Low Evidence).
Congenital myopathy v6.7 SRPK3 Arina Puzriakova Phenotypes for gene: SRPK3 were changed from Slowly progressive myopathy to Slowly progressive myopathy, digenic
Congenital myopathy v6.6 SRPK3 Arina Puzriakova Publications for gene: SRPK3 were set to 26799446
Congenital myopathy v6.5 SRPK3 Arina Puzriakova Phenotypes for gene: SRPK3 were changed from Nemaline myopathy, MONDO:0018958 to Slowly progressive myopathy
Congenital myopathy v6.4 SRPK3 Arina Puzriakova Tag digenic tag was added to gene: SRPK3.
Congenital myopathy v6.4 SRPK3 Arina Puzriakova reviewed gene: SRPK3: Rating: ; Mode of pathogenicity: None; Publications: 16140986, 38429495, 39667923; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Cytopenia - NOT Fanconi anaemia v4.9 FASLG Achchuthan Shanmugasundram Classified gene: FASLG as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v4.9 FASLG Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic FASLG variants with ALPS, which has cytopenia as presenting phenotype. Hence, this gene can be promoted to green rating in the next GMS update.
Cytopenia - NOT Fanconi anaemia v4.9 FASLG Achchuthan Shanmugasundram Gene: faslg has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v4.8 FASLG Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: FASLG.
Cytopenia - NOT Fanconi anaemia v4.8 FASLG Achchuthan Shanmugasundram Phenotypes for gene: FASLG were changed from ALPS to Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859
Cytopenia - NOT Fanconi anaemia v4.7 FASLG Achchuthan Shanmugasundram Publications for gene: FASLG were set to
Cytopenia - NOT Fanconi anaemia v4.6 FASLG Achchuthan Shanmugasundram Mode of inheritance for gene: FASLG was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v4.5 FASLG Achchuthan Shanmugasundram reviewed gene: FASLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 8787672, 16627752, 17605793, 25451160, 26334989; Phenotypes: Autoimmune lymphoproliferative syndrome, type IB, OMIM:601859; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v4.5 FAS Achchuthan Shanmugasundram changed review comment from: FAS has a well-established gene-disease association for autosomal dominant autoimmune lymphoproliferative syndrome (ALPS) in OMIM (MIM #601859) and Gene2Phenotype (with 'definitive' rating on 'Skin disorders' panel). OMIM also reported autoimmune hemolytic anemia, thrombocytopenia and neutropenia as clinical presentations of this disorder.

This gene has also been associated with biallelic ALPS syndrome in Gene2Phenotype (with 'definitive' rating on 'Skin disorders' panel).

PMID:34171534 reviewed evidence from previously published reports, which showed that there is sufficient evidence available for the association of both monoallelic and biallelic germline variants with ALPS syndrome. There is also sufficient evidence available for the presence of autoimmune cytopenias (hemolytic anemia, thrombocytopenia and neutropenia) in both patients with both monoallelic and biallelic variants.; to: FAS has a well-established gene-disease association for autoimmune lymphoproliferative syndrome (ALPS). Both germline and somatic variants have been reported to cause ALPS.

FAS has been associated with autosomal dominant ALPS in OMIM (MIM #601859) and Gene2Phenotype (with 'definitive' rating on 'Skin disorders' panel). OMIM also reports autoimmune hemolytic anemia, thrombocytopenia and neutropenia as clinical presentations of this disorder.

This gene has also been associated with autosomal recessive ALPS syndrome in Gene2Phenotype (with 'definitive' rating on 'Skin disorders' panel).

PMID:34171534 reviewed evidence from previously published reports, which showed that there is sufficient evidence available for the association of both monoallelic and biallelic germline variants with ALPS syndrome. There is also sufficient evidence available for the presence of autoimmune cytopenias (hemolytic anemia, thrombocytopenia and neutropenia) in both patients with both monoallelic and biallelic variants.
Cytopenia - NOT Fanconi anaemia v4.5 FAS Achchuthan Shanmugasundram Classified gene: FAS as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v4.5 FAS Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants with autoimmune cytopenia. Hence, this gene can be promoted to green rating in the next GMS update.
Cytopenia - NOT Fanconi anaemia v4.5 FAS Achchuthan Shanmugasundram Gene: fas has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v4.4 FAS Achchuthan Shanmugasundram Phenotypes for gene: FAS were changed from ALPS to Autoimmune lymphoproliferative syndrome, type IA, OMIM:601859
Cytopenia - NOT Fanconi anaemia v4.3 FAS Achchuthan Shanmugasundram Publications for gene: FAS were set to
Cytopenia - NOT Fanconi anaemia v4.2 FAS Achchuthan Shanmugasundram Mode of inheritance for gene: FAS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v4.1 FAS Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: FAS.
Cytopenia - NOT Fanconi anaemia v4.1 FAS Achchuthan Shanmugasundram reviewed gene: FAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 34171534; Phenotypes: Autoimmune lymphoproliferative syndrome, type IA, OMIM:601859; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.26 SRPK3 Arina Puzriakova Phenotypes for gene: SRPK3 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Intellectual developmental disorder, X-linked 114, OMIM:301134
Cholestasis v3.7 RINT1 Achchuthan Shanmugasundram reviewed gene: RINT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31204009, 37463447, 39186236; Phenotypes: Infantile liver failure syndrome 3, OMIM:618641; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v6.4 TNNT1 Arina Puzriakova commented on gene: TNNT1: - PMID: 25430424 (2015) - 2 year old Hispanic male diagnosed with nemaline myopathy and a homozygous variant c.323C>G (p.S108X) in the TNNT1 gene. Patient had low muscle tone, global muscle weakness (proximal more than distal), hip and knee contractures and developmental delay. Muscle biopsy confirmed nemaline myopathy.

- PMID: 12732643 (2003) - a lethal form of nemaline myopathy (known as ANM - Amish nemaline myopathy) found in family with a homozygous nonsense variant Glu180 in TNNT1 (previously known as TNT). ANM presents with tremors at birth, proximal contractures and hypotonia, and progressive weakness often leading to death from respiratory insufficiency.
Congenital myopathy v6.4 TNNI1 Arina Puzriakova Phenotypes for gene: TNNI1 were changed from Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease to Hypocontractile muscle disease
Congenital myopathy v6.3 TNNI1 Arina Puzriakova Mode of inheritance for gene: TNNI1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v6.2 TNNI1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. 3 families with biallelic LOF variants and 3 families with monoallelic GOF variants, presenting with a hypo- or hypercontractile phenotype, respectively.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. 3 families with biallelic LOF variants and 3 families with monoallelic GOF variants, presenting with a hypo- or hypercontractile phenotype, respectively.

However, the biallelic phenotype is early onset and more severe, thus is the only MOI relevant to this panel as severe congenital cases are more likely to be tested under this clinical indication.
Congenital myopathy v6.2 TNNI1 Arina Puzriakova edited their review of gene: TNNI1: Changed phenotypes to: Hypocontractile (AR LOF) muscle disease; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v6.2 TNNI1 Arina Puzriakova Entity copied from Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7
Congenital myopathy v6.2 TNNI1 Arina Puzriakova gene: TNNI1 was added
gene: TNNI1 was added to Congenital myopathy. Sources: Literature,Expert Review Amber
Q2_25_ promote_green tags were added to gene: TNNI1.
Mode of inheritance for gene: TNNI1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: TNNI1 were set to 38569017; 34934811
Phenotypes for gene: TNNI1 were set to Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7 TNNI1 Arina Puzriakova Classified gene: TNNI1 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7 TNNI1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. 3 families with biallelic LOF variants and 3 families with monoallelic GOF variants, presenting with a hypo- or hypercontractile phenotype, respectively.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.7 TNNI1 Arina Puzriakova Gene: tnni1 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.6 TNNI1 Arina Puzriakova Mode of inheritance for gene: TNNI1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.5 TNNI1 Arina Puzriakova Phenotypes for gene: TNNI1 were changed from Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease to Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.4 TNNI1 Arina Puzriakova Phenotypes for gene: TNNI1 were changed from to Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.4 TNNI1 Arina Puzriakova Publications for gene: TNNI1 were set to PMID: 38569017
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3 TNNI1 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: TNNI1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3 TNNI1 Arina Puzriakova changed review comment from: - PMID: 38569017 (2024) - 9 individuals from 3 families with biallelic LOF variants in the TNNI1 gene, manifesting with early-onset myopathy with progressive muscle weakness (proximal more than distal) and rod formation on histology. 2 individuals from different families presented with severe infantile weakness with minimal attainment of motor milestones. 3 individuals from 2 families had mild/moderate contractures.

Also another 2 families with heterozygous GOF variants, resulting in hypercontractile disease with a constellation of symptoms
including muscle cramping, myalgias, stiffness, and rod formation. 4/5 patients reported normal muscle strength and there is no mention of contractures. Recognition of symptoms ranged from childhood to adulthood.

Functional studies in zebrafish demonstrate variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype.


- PMID: 34934811 (2021) - Japanese family with 3 affected individuals with proximal arthrogryposis and elevated CK, albeit without muscle weakness. A presumed GOF heterozygous c.523A>T, p.K175* TNNI1 variant was identified (2 genotyped). Muscle biopsy demonstrated a moth-eaten appearance and mild fibre size variation in type 1 fibres, and electron microscopic analysis revealed type 1 fibre Z disk streaming. No functional studies were done.; to: - PMID: 38569017 (2024) - 9 individuals from 3 families with biallelic LOF variants in the TNNI1 gene, manifesting with early-onset myopathy with progressive muscle weakness (proximal more than distal) and rod formation on histology. 2 individuals from different families presented with severe infantile weakness with minimal attainment of motor milestones. 3 individuals from 2 families had mild/moderate contractures.

Also another 2 families with heterozygous GOF variants, resulting in hypercontractile disease with a constellation of symptoms including muscle cramping, myalgias, stiffness, and rod formation. 4/5 patients reported normal muscle strength and there is no mention of contractures. Recognition of symptoms ranged from childhood to adulthood.

Functional studies in zebrafish demonstrate variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype.


- PMID: 34934811 (2021) - Japanese family with 3 affected individuals with proximal arthrogryposis and elevated CK, albeit without muscle weakness. A presumed GOF heterozygous c.523A>T, p.K175* TNNI1 variant was identified (2 genotyped). Muscle biopsy demonstrated a moth-eaten appearance and mild fibre size variation in type 1 fibres, and electron microscopic analysis revealed type 1 fibre Z disk streaming. No functional studies were done.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3 TNNI1 Arina Puzriakova reviewed gene: TNNI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38569017, 34934811; Phenotypes: Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Severe early-onset obesity v5.16 STX16 Achchuthan Shanmugasundram Classified gene: STX16 as Amber List (moderate evidence)
Severe early-onset obesity v5.16 STX16 Achchuthan Shanmugasundram Gene: stx16 has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v5.15 STX16 Achchuthan Shanmugasundram Publications for gene: STX16 were set to PMID: 27338644; 28453643
Severe early-onset obesity v5.14 STX16 Achchuthan Shanmugasundram Phenotypes for gene: STX16 were changed from Obesity with pseudohypoparathyroidism type 1B to Pseudohypoparathyroidism, type IB OMIM:603233; Obesity, HP:0001513
Severe early-onset obesity v5.13 STX16 Achchuthan Shanmugasundram Mode of inheritance for gene: STX16 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Severe early-onset obesity v5.12 STX16 Achchuthan Shanmugasundram edited their review of gene: STX16: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Severe early-onset obesity v5.12 STX16 Achchuthan Shanmugasundram changed review comment from: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion.

PMID:28453643 reported five patients reported with obesity with onset ranging from 3-12 months of age. Deletion of STX16 gene (either 3-kb or 4.4-kb) was reported in these cases confirming genetic diagnosis of Pseudohypoparathyroidism, type IB. All these patients inherited STX16 deletions from their unaffected mothers, and these deletions reside on paternal allele of these mothers. This indicates that maternally inherited deletions are associated with the phenotype. Excessive weight gain preceded other clinical or laboratory signs of PHP1B by more than a decade in some patients. One of these patients had symptomatic hypocalcemia and elevated PTH levels when admitted to hospital at 11.5 years, and another was reported with asymptomatic hypocalcemia and an elevated PTH level only after establishing the genetic defect.

As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years and in the absence of significant features.

All the cases reported above had early onset obesity before the age of 5 and appears severe. However, the patient from PMID:27338644 had other presentations such as macrosomia and macrocephaly suggesting the phenotype is syndromic. Although some of the cases reported in PMID:28453643 had hypocalcemia and an elevated PTH level, their onset was much later than that of obesity. Hence, it is useful to include this gene on this panel to get diagnosis for patients early in their life and before the onset of PHP1B. Clinical opinion is therefore sought in relation to promoting this gene to green rating on this panel.



; to: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion.

PMID:28453643 reported five patients reported with obesity with onset ranging from 3-12 months of age. Deletion of STX16 gene (either 3-kb or 4.4-kb) was reported in these cases confirming genetic diagnosis of Pseudohypoparathyroidism, type IB. All these patients inherited STX16 deletions from their unaffected mothers, and these deletions reside on paternal allele of these mothers. This indicates that maternally inherited deletions are associated with the phenotype. Excessive weight gain preceded other clinical or laboratory signs of PHP1B by more than a decade in some patients. One of these patients had symptomatic hypocalcemia and elevated PTH levels when admitted to hospital at 11.5 years, and another was reported with asymptomatic hypocalcemia and an elevated PTH level only after establishing the genetic defect.

As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years and in the absence of significant features.

All the cases reported above had early onset obesity before the age of 5 and appears severe. However, the patient from PMID:27338644 had other presentations such as macrosomia and macrocephaly suggesting the phenotype is syndromic. Although some of the cases reported in PMID:28453643 had hypocalcemia and an elevated PTH level, their onset was much later than that of obesity. Hence, it is useful to include this gene on this panel to get diagnosis for patients early in their life and before the onset of PHP1B. Clinical opinion is therefore sought in relation to promoting this gene to green rating on this panel.
Severe early-onset obesity v5.12 STX16 Achchuthan Shanmugasundram changed review comment from: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion.; to: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion.

PMID:28453643 reported five patients reported with obesity with onset ranging from 3-12 months of age. Deletion of STX16 gene (either 3-kb or 4.4-kb) was reported in these cases confirming genetic diagnosis of Pseudohypoparathyroidism, type IB. All these patients inherited STX16 deletions from their unaffected mothers, and these deletions reside on paternal allele of these mothers. This indicates that maternally inherited deletions are associated with the phenotype. Excessive weight gain preceded other clinical or laboratory signs of PHP1B by more than a decade in some patients. One of these patients had symptomatic hypocalcemia and elevated PTH levels when admitted to hospital at 11.5 years, and another was reported with asymptomatic hypocalcemia and an elevated PTH level only after establishing the genetic defect.

As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf) the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years and in the absence of significant features.

All the cases reported above had early onset obesity before the age of 5 and appears severe. However, the patient from PMID:27338644 had other presentations such as macrosomia and macrocephaly suggesting the phenotype is syndromic. Although some of the cases reported in PMID:28453643 had hypocalcemia and an elevated PTH level, their onset was much later than that of obesity. Hence, it is useful to include this gene on this panel to get diagnosis for patients early in their life and before the onset of PHP1B. Clinical opinion is therefore sought in relation to promoting this gene to green rating on this panel.
Likely inborn error of metabolism v8.55 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from X-linked adrenoleukodystrophy (Disorders of peroxisomal alpha-, beta and omega-oxidation); Adrenoleukodystrophy 300100 to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
Intellectual disability v9.25 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Adrenoleukodystrophy, 300100; Adrenomyeloneuropathy, adult, 300100; ADRENOLEUKODYSTROPHY, X-LINKED to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
Hereditary neuropathy or pain disorder v7.2 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Adrenoleukodystrophy, OMIM:300100; Adrenomyeloneuropathy, adult, OMIM:300100; adrenoleukodystrophy, MONDO:0018544 to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
Undiagnosed metabolic disorders v1.630 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from X-linked adrenoleukodystrophy (Disorders of peroxisomal alpha-, beta and omega-oxidation); Adrenoleukodystrophy 300100 to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
Adult onset neurodegenerative disorder v8.2 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Hereditary spastic paraplegia, MONDO:0019064; adrenal failure; VLCFA accumulation; spastic paraparesis to Adrenoleukodystrophy, adult, OMIM:300100
Adult onset hereditary spastic paraplegia v6.2 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from spastic paraparesis; Hereditary spastic paraplegia; adrenal failure; VLCFA accumulation; Adrenoleukodystrophy, 300100 to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100; Adrenal failure; VLCFA accumulation; Spastic paraparesis
Childhood onset hereditary spastic paraplegia v8.2 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from spastic paraparesis; VLCFA accumulation; adrenal failure; Hereditary spastic paraplegia to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100; Adrenal failure; VLCFA accumulation; Spastic paraparesis
Hereditary spastic paraplegia v1.315 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Hereditary spastic paraplegia; adrenal failure; VLCFA accumulation; spastic paraparesis; Adrenoleukodystrophy, 300100 to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100; Adrenal failure; VLCFA accumulation; Spastic paraparesis
Inherited white matter disorders v1.185 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Adrenoleukodystrophy, 300100; Adrenomyeloneuropathy, adult, 300100; X-Linked Adrenoleukodystrophy; Adrenoleukodystrophy, X-linked; Adrenoleukodystrophy to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
White matter disorders and cerebral calcification - narrow panel v7.4 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from Adrenomyeloneuropathy, adult, 300100; Adrenoleukodystrophy, X-linked; Adrenoleukodystrophy; Adrenoleukodystrophy, 300100; X-Linked Adrenoleukodystrophy to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
Congenital adrenal hypoplasia v4.5 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from X-linked adrenoleukodystrophy to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100
Congenital adrenal hypoplasia v4.4 ABCD1 Arina Puzriakova Publications for gene: ABCD1 were set to
Congenital adrenal hypoplasia v4.3 ABCD1 Arina Puzriakova Classified gene: ABCD1 as Amber List (moderate evidence)
Congenital adrenal hypoplasia v4.3 ABCD1 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update as its plausible that ABCD1-related adrenoleukodystrophy, which presents with adrenal insufficiency, could be tested under this panel.
Congenital adrenal hypoplasia v4.3 ABCD1 Arina Puzriakova Gene: abcd1 has been classified as Amber List (Moderate Evidence).
Congenital adrenal hypoplasia v4.2 ABCD1 Arina Puzriakova Mode of inheritance for gene: ABCD1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital adrenal hypoplasia v4.1 ABCD1 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: ABCD1.
Pulmonary arterial hypertension v4.4 CAPNS1 Arina Puzriakova Tag watchlist tag was added to gene: CAPNS1.
Pulmonary arterial hypertension v4.4 CAPNS1 Arina Puzriakova Classified gene: CAPNS1 as Amber List (moderate evidence)
Pulmonary arterial hypertension v4.4 CAPNS1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber with watchlist tag - 2 unrelated cases (2 Tunisian sibs, 1 Dutch man) have been identified with homozygous variants in this gene and severe pulmonary arterial hypertension. RNA sequencing demonstrated aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. Additional case required before promotion to Green.
Pulmonary arterial hypertension v4.4 CAPNS1 Arina Puzriakova Gene: capns1 has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v4.3 CAPNS1 Arina Puzriakova Publications for gene: CAPNS1 were set to PMID:38230350
Pulmonary arterial hypertension v4.2 CAPNS1 Arina Puzriakova Phenotypes for gene: CAPNS1 were changed from pulmonary arterial hypertension to Pulmonary hypertension, primary, 6, OMIM:620777
Inherited bleeding disorders v1.181 PLG Arina Puzriakova Publications for gene: PLG were set to
Inherited bleeding disorders v1.180 PLG Arina Puzriakova Classified gene: PLG as Red List (low evidence)
Inherited bleeding disorders v1.180 PLG Arina Puzriakova Added comment: Comment on list classification: PLG deficiency causes hypoplasminogenemia characterised by chronic pseudomembranous lesions consisting of fibrin deposition and inflammation, with ligneous conjunctivitis being the predominant clinical feature.

Predisposition to thrombosis was indicated in knockout mice which develop spontaneous, severe thromboses in multiple organs (PMID: 7705657). However, studies in humans have shown that severe PLG deficiency is rare and only weakly associated with thrombosis, largely in combination with other risk factors (PMID: 9684804; 12850227; 16849641; 27976734).

Overall the evidence indicates that this gene should be demoted from Green to Amber/Red.
Inherited bleeding disorders v1.180 PLG Arina Puzriakova Gene: plg has been classified as Red List (Low Evidence).
Thrombophilia with a likely monogenic cause v2.7 PLG Arina Puzriakova changed review comment from: Comment on list classification: PLG deficiency causes hypoplasminogenemia characterised by chronic pseudomembranous lesions consisting of fibrin deposition and inflammation, with ligneous conjunctivitis being the predominant clinical feature.


Predisposition to thrombosis was indicated in knockout mice which develop spontaneous, severe thromboses in multiple organs (PMID: 7705657). However, studies in humans have shown that severe PLG deficiency is rare and only weakly associated with thrombosis, largely in combination with other risk factors (PMID: 9684804; 12850227; 16849641; 27976734).

Overall the evidence indicates that this gene should be demoted from Green to Amber/Red at the next GMS panel update.; to: Comment on list classification: PLG deficiency causes hypoplasminogenemia characterised by chronic pseudomembranous lesions consisting of fibrin deposition and inflammation, with ligneous conjunctivitis being the predominant clinical feature.

Predisposition to thrombosis was indicated in knockout mice which develop spontaneous, severe thromboses in multiple organs (PMID: 7705657). However, studies in humans have shown that severe PLG deficiency is rare and only weakly associated with thrombosis, largely in combination with other risk factors (PMID: 9684804; 12850227; 16849641; 27976734).

Overall the evidence indicates that this gene should be demoted from Green to Amber/Red at the next GMS panel update.
Thrombophilia with a likely monogenic cause v2.7 PLG Arina Puzriakova Publications for gene: PLG were set to
Thrombophilia with a likely monogenic cause v2.6 PLG Arina Puzriakova Classified gene: PLG as Green List (high evidence)
Thrombophilia with a likely monogenic cause v2.6 PLG Arina Puzriakova Added comment: Comment on list classification: PLG deficiency causes hypoplasminogenemia characterised by chronic pseudomembranous lesions consisting of fibrin deposition and inflammation, with ligneous conjunctivitis being the predominant clinical feature.


Predisposition to thrombosis was indicated in knockout mice which develop spontaneous, severe thromboses in multiple organs (PMID: 7705657). However, studies in humans have shown that severe PLG deficiency is rare and only weakly associated with thrombosis, largely in combination with other risk factors (PMID: 9684804; 12850227; 16849641; 27976734).

Overall the evidence indicates that this gene should be demoted from Green to Amber/Red at the next GMS panel update.
Thrombophilia with a likely monogenic cause v2.6 PLG Arina Puzriakova Gene: plg has been classified as Green List (High Evidence).
Thrombophilia with a likely monogenic cause v2.5 PLG Arina Puzriakova Tag Q2_25_expert_review tag was added to gene: PLG.
Tag Q2_25_ demote_amber tag was added to gene: PLG.
Amelogenesis imperfecta v4.5 LAMC2 Eleanor Williams Classified gene: LAMC2 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.5 LAMC2 Eleanor Williams Added comment: Comment on list classification: Keeping the rating as amber. 1 reported case (PMID: 37228816) but with no phenotype for the mother who also carries the variant in LAMC2. Supportive mouse model in (PMID:26956061).
Amelogenesis imperfecta v4.5 LAMC2 Eleanor Williams Gene: lamc2 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.4 LAMC2 Eleanor Williams Phenotypes for gene: LAMC2 were changed from Amelogenesis Imperfecta; Epidermolysis bullosa, junctional, Herlitz type, 226700; Epidermolysis bullosa, junctional, non-Herlitz type, 226650 to amelogenesis imperfecta, MONDO:0019507
Amelogenesis imperfecta v4.3 LAMC2 Eleanor Williams Added comment: Comment on mode of inheritance: Updating the mode of inheritance to monoallelic since in the only reported case the proband was heterozygous for a variant in LAMC2.
Amelogenesis imperfecta v4.3 LAMC2 Eleanor Williams Mode of inheritance for gene: LAMC2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Amelogenesis imperfecta v4.2 LAMC2 Eleanor Williams Publications for gene: LAMC2 were set to 26956061
Pigmentary skin disorders v4.3 SMARCB1 Eleanor Williams changed review comment from: Comment on list classification: Since cafe-au-lait or other pigmentary changes do not appear to be common in Schwannomatosis-1, or the presenting feature, this gene has been rated amber on this panel.; to: Comment on list classification: Since cafe-au-lait or other pigmentary changes do not appear to be common in Schwannomatosis-1, or the presenting feature, this gene has been rated red on this panel.
Pigmentary skin disorders v4.3 SMARCB1 Eleanor Williams Classified gene: SMARCB1 as Red List (low evidence)
Pigmentary skin disorders v4.3 SMARCB1 Eleanor Williams Gene: smarcb1 has been classified as Red List (Low Evidence).
Pigmentary skin disorders v4.2 SMARCB1 Eleanor Williams Classified gene: SMARCB1 as Amber List (moderate evidence)
Pigmentary skin disorders v4.2 SMARCB1 Eleanor Williams Added comment: Comment on list classification: Since cafe-au-lait or other pigmentary changes do not appear to be common in Schwannomatosis-1, or the presenting feature, this gene has been rated amber on this panel.
Pigmentary skin disorders v4.2 SMARCB1 Eleanor Williams Gene: smarcb1 has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v4.1 SMARCB1 Eleanor Williams reviewed gene: SMARCB1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pigmentary skin disorders v4.1 BLM Eleanor Williams edited their review of gene: BLM: Changed publications to: 7485150
Pigmentary skin disorders v4.1 BLM Eleanor Williams reviewed gene: BLM: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v4.5 CBS Arina Puzriakova changed review comment from: Individuals with CBS variants are at higher of thromboembolic events such as peripheral vein thrombosis, pulmonary embolism, stroke, peripheral artery occlusion, and myocardial infarction. Cerebral sinovenous thrombosis can occur but could not find evidence of vascular malformations. Therefore this gene does not appear relevant to this panel and rating as Red.; to: Individuals with CBS variants are at higher risk of thromboembolic events such as peripheral vein thrombosis, pulmonary embolism, stroke, peripheral artery occlusion, and myocardial infarction. Cerebral sinovenous thrombosis can occur but could not find evidence of vascular malformations. Therefore this gene does not appear relevant to this panel and rating as Red.
Cerebral vascular malformations v4.5 CBS Arina Puzriakova Classified gene: CBS as Red List (low evidence)
Cerebral vascular malformations v4.5 CBS Arina Puzriakova Gene: cbs has been classified as Red List (Low Evidence).
Cerebral vascular malformations v4.4 CBS Arina Puzriakova commented on gene: CBS
Primary lymphoedema v4.3 TIE1 Arina Puzriakova Classified gene: TIE1 as Amber List (moderate evidence)
Primary lymphoedema v4.3 TIE1 Arina Puzriakova Added comment: Comment on list classification: At least 6 families have been reported in literature with heterozygous variants in this gene and lymphedema which support inclusion on this panel with a Green rating at the next GMS panel update.
Primary lymphoedema v4.3 TIE1 Arina Puzriakova Gene: tie1 has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v4.2 TIE1 Arina Puzriakova Tag watchlist was removed from gene: TIE1.
Tag Q2_25_ promote_green tag was added to gene: TIE1.
Primary lymphoedema v4.2 TIE1 Arina Puzriakova commented on gene: TIE1
Primary lymphoedema v4.2 TIE1 Arina Puzriakova Publications for gene: TIE1 were set to 32947856; 24764452
Intellectual disability v9.24 PDE1B Sarah Dixon gene: PDE1B was added
gene: PDE1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE1B were set to PMID: 40492975
Phenotypes for gene: PDE1B were set to hypotonia; ataxia; dystonia; developmental delay; intellectual disability
Penetrance for gene: PDE1B were set to unknown
Review for gene: PDE1B was set to GREEN
Added comment: PMID: 40492975
Biallelic LOF variants in PDE1B identified in seven individuals from five different families
Disorder characterized by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with developmental delay and intellectual disability
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.4 PDE1B Sarah Dixon gene: PDE1B was added
gene: PDE1B was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE1B were set to PMID: 40492975
Phenotypes for gene: PDE1B were set to hypotonia; ataxia; dystonia; developmental delay; intellectual disability
Penetrance for gene: PDE1B were set to unknown
Review for gene: PDE1B was set to GREEN
Added comment: PMID: 40492975
Biallelic LOF variants in PDE1B identified in seven individuals from five different families
Disorder characterized by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with developmental delay and intellectual disability
Sources: Literature
DDG2P v6.1 PDE1B Sarah Dixon gene: PDE1B was added
gene: PDE1B was added to DDG2P. Sources: Literature
Mode of inheritance for gene: PDE1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE1B were set to PMID: 40492975
Phenotypes for gene: PDE1B were set to hypotonia; ataxia; dystonia; developmental delay; intellectual disability
Penetrance for gene: PDE1B were set to unknown
Review for gene: PDE1B was set to GREEN
Added comment: PMID: 40492975
Biallelic LOF variants in PDE1B identified in seven individuals from five different families
Disorder characterized by hypotonia in infancy, progressing to ataxia and dystonia in early childhood, with developmental delay and intellectual disability
Sources: Literature
Severe early-onset obesity v5.12 STX16 Achchuthan Shanmugasundram commented on gene: STX16: PMID:27338644 reported a female infant presenting with macrocosmia, early-onset obesity and macrocephaly. The patient had a BMI of +3.7 SD for the age at 1.5 years. She was identified with a previously described recurrent 3-kb STX16 deletion.
Severe early-onset obesity v5.12 STX16 Achchuthan Shanmugasundram reviewed gene: STX16: Rating: GREEN; Mode of pathogenicity: None; Publications: 27338644, 28453643; Phenotypes: Pseudohypoparathyroidism, type IB OMIM:603233, Obesity, HP:0001513; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe early-onset obesity v5.12 MRAP2 Achchuthan Shanmugasundram Phenotypes for gene: MRAP2 were changed from obesity; {?Obesity, susceptibility to, BMIQ18}; Prader-Willi syndrome to {?Obesity, susceptibility to, BMIQ18}, OMIM:615457
Severe early-onset obesity v5.11 MRAP2 Achchuthan Shanmugasundram Publications for gene: MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls, nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a 10-year old boy with overall obesity in combination with intellectual disability in a screen of Prader-Willi syndrome (PWS) patients. The clinically diagnosed PWS could not be confirmed molecularly with MS-MLPA and CNV analysis of the 6q14.1–q16.3 region also showed no deletions in this patient. No further family data were available to determine whether the variant segregates with obesity in this family. It was shown to be (probably) damaging by in silico analysis and found in only one European (non-Finnish) individual in the ExAC database (since this database cannot release phenotype information about the screened individuals, no conclusions regarding causality of this variant can be drawn).
Severe early-onset obesity v5.10 MRAP2 Achchuthan Shanmugasundram reviewed gene: MRAP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 23869016, 26795956, 27474872, 31700171; Phenotypes: {?Obesity, susceptibility to, BMIQ18}, OMIM:615457; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe early-onset obesity v5.10 MC3R Achchuthan Shanmugasundram Classified gene: MC3R as Red List (low evidence)
Severe early-onset obesity v5.10 MC3R Achchuthan Shanmugasundram Gene: mc3r has been classified as Red List (Low Evidence).
Severe early-onset obesity v5.9 MC3R Achchuthan Shanmugasundram Phenotypes for gene: MC3R were changed from obesity to {Obesity, severe, susceptibility to, BMIQ9}, OMIM:602025
Severe early-onset obesity v5.8 MC3R Achchuthan Shanmugasundram Publications for gene: MC3R were set to PMID: 31090190
Severe early-onset obesity v5.7 MC3R Achchuthan Shanmugasundram edited their review of gene: MC3R: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe early-onset obesity v5.7 MC3R Achchuthan Shanmugasundram reviewed gene: MC3R: Rating: RED; Mode of pathogenicity: None; Publications: 31090190; Phenotypes: {Obesity, severe, susceptibility to, BMIQ9}, OMIM:602025; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe early-onset obesity v5.7 TRPC5 Achchuthan Shanmugasundram Classified gene: TRPC5 as Amber List (moderate evidence)
Severe early-onset obesity v5.7 TRPC5 Achchuthan Shanmugasundram Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v5.6 TRPC5 Achchuthan Shanmugasundram Phenotypes for gene: TRPC5 were changed from obesity to Obesity, HP:0001513
Severe early-onset obesity v5.5 TRPC5 Achchuthan Shanmugasundram Publications for gene: TRPC5 were set to PMID: 38959890
Severe early-onset obesity v5.4 TRPC5 Achchuthan Shanmugasundram reviewed gene: TRPC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 38959890; Phenotypes: Obesity, HP:0001513; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Thoracic aortic aneurysm or dissection (GMS) v4.2 COL3A1 Arina Puzriakova Phenotypes for gene: COL3A1 were changed from Ehlers-Danlos syndrome, type IV, 130050; Loeys-Dietz syndrome; Ehlers-Danlos syndrome, vascular type (130050) to Ehlers-Danlos syndrome, vascular type, OMIM:130050; Polymicrogyria with or without vascular-type EDS, OMIM:618343
Thoracic aortic aneurysm or dissection v1.128 COL3A1 Arina Puzriakova Phenotypes for gene: COL3A1 were changed from Loeys-Dietz syndrome; Ehlers-Danlos syndrome, type IV, 130050; Ehlers-Danlos syndrome, vascular type (130050) to Ehlers-Danlos syndrome, vascular type, OMIM:130050; Polymicrogyria with or without vascular-type EDS, OMIM:618343
Bleeding and platelet disorders v4.2 COL3A1 Arina Puzriakova Phenotypes for gene: COL3A1 were changed from Ehlers-Danlos syndrome, vascular type, 130050 to Ehlers-Danlos syndrome, vascular type, OMIM:130050; Polymicrogyria with or without vascular-type EDS, OMIM:618343
Fetal anomalies v6.6 COL3A1 Arina Puzriakova Phenotypes for gene: COL3A1 were changed from HP:0002126; HP:0001883; HP:0006496 to Ehlers-Danlos syndrome, vascular type, OMIM:130050; Polymicrogyria with or without vascular-type EDS, OMIM:618343
Ehlers Danlos syndrome with a likely monogenic cause v4.2 COL3A1 Arina Puzriakova Phenotypes for gene: COL3A1 were changed from Ehlers-Danlos syndrome, vascular type, OMIM:130050 to Ehlers-Danlos syndrome, vascular type, OMIM:130050; Polymicrogyria with or without vascular-type EDS, OMIM:618343
Primary ciliary disorders v1.45 WFDC2 Arina Puzriakova Publications for gene: WFDC2 were set to 38626355
Primary ciliary disorders v1.44 WFDC2 Arina Puzriakova Classified gene: WFDC2 as Red List (low evidence)
Primary ciliary disorders v1.44 WFDC2 Arina Puzriakova Added comment: Comment on list classification: PMID: 38626355; 4040104214 - individuals from 14 families have been reported with biallelic variants in this gene and bronchiectasis, nasal polyposis and sinopulmonary disease. Ciliary structure, beat frequency and coordination, as well as mucus viscosity were all within normal range and therefore this gene does not seem relevant to this panel. Rating Red.
Primary ciliary disorders v1.44 WFDC2 Arina Puzriakova Gene: wfdc2 has been classified as Red List (Low Evidence).
Autoinflammatory disorders v2.29 RIPK1 Achchuthan Shanmugasundram Classified gene: RIPK1 as Amber List (moderate evidence)
Autoinflammatory disorders v2.29 RIPK1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dorota Rowczenio, there is sufficient evidence available for the association of both monoallelic and biallelic variants in RIPK1 gene with autoinflammatory disease phenotypes (MIMs #618852 & 618108). Hence, this gene can be promoted to green rating in the next GMS update.
Autoinflammatory disorders v2.29 RIPK1 Achchuthan Shanmugasundram Gene: ripk1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.18 RIPK1 Achchuthan Shanmugasundram Phenotypes for gene: RIPK1 were changed from Immunodeficiency 57, 618108; Severe immunodeficiency, arthritis, and intestinal inflammation to Autoinflammation with episodic fever and lymphadenopathy, OMIM:618852; Immunodeficiency 57 with autoinflammation, OMIM: 618108
Respiratory ciliopathies including non-CF bronchiectasis v4.4 WFDC2 Arina Puzriakova Publications for gene: WFDC2 were set to 38626355
Autoinflammatory disorders v2.28 RIPK1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: RIPK1.
Tag Q2_25_ NHS_review tag was added to gene: RIPK1.
Autoinflammatory disorders v2.28 RIPK1 Achchuthan Shanmugasundram Phenotypes for gene: RIPK1 were changed from Autoinflammation with episodic fever and lymphadenopathy (autosomal dominant); Immunodeficiency 57 with autoinflammation (autosomal recessive) to Autoinflammation with episodic fever and lymphadenopathy, OMIM:618852; Immunodeficiency 57 with autoinflammation, OMIM: 618108
Autoinflammatory disorders v2.27 RIPK1 Achchuthan Shanmugasundram Publications for gene: RIPK1 were set to PMID: 31911632; PMID: 31827281; PMID:31827280; PMID: 39557292; PMID: 37452601; PMID:35716229; PMID:35786329
Autoinflammatory disorders v2.26 RIPK1 Achchuthan Shanmugasundram reviewed gene: RIPK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30026316, 31827280, 31827281, 31911632, 35716229, 35786329, 39557292; Phenotypes: Autoinflammation with episodic fever and lymphadenopathy, OMIM:618852, Immunodeficiency 57 with autoinflammation, OMIM: 618108; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary ciliary disorders v1.43 WFDC2 Arina Puzriakova Phenotypes for gene: WFDC2 were changed from Nasal Polyposis; Bronchiectasis to Bronchiectasis and nasal polyposis, OMIM:620984
Respiratory ciliopathies including non-CF bronchiectasis v4.3 WFDC2 Arina Puzriakova Phenotypes for gene: WFDC2 were changed from bronchiectasis, MONDO:0004822; Nasal polyposis, HP:0100582 to Bronchiectasis and nasal polyposis, OMIM:620984
Autoinflammatory disorders v2.26 RELA Arina Puzriakova Publications for gene: RELA were set to PMID: 36926348; PMID: 32969189; PMID: 35412596; PMID: 28600438
Autoinflammatory disorders v2.25 RELA Arina Puzriakova Tag Q2_23_NHS_review was removed from gene: RELA.
Tag Q2_25_ NHS_review tag was added to gene: RELA.
Autoinflammatory disorders v2.25 RELA Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: RELA.
Tag Q2_23_NHS_review tag was added to gene: RELA.
Autoinflammatory disorders v2.25 RELA Arina Puzriakova Classified gene: RELA as Amber List (moderate evidence)
Autoinflammatory disorders v2.25 RELA Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

At least 7 unrelated cases identified in literature with monoallelic RELA variants and Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287 which is characterised predominantly by intermittent fevers and chronic mucocutaneous ulceration although clinical presentation can be variable.
Autoinflammatory disorders v2.25 RELA Arina Puzriakova Gene: rela has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.17 TBK1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed before, there is sufficient evidence available for the association of monoallelic TBK1 variants to this panel based on {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8} phenotype (MIM #617900).

There is sufficient evidence available now (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder (MIM # 620880).

Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.17 TBK1 Achchuthan Shanmugasundram Mode of inheritance for gene: TBK1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v8.16 TBK1 Achchuthan Shanmugasundram Phenotypes for gene: TBK1 were changed from Herpes simplex encephalitis, susceptibility to; Herpetic encephalitis (HSE); {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8} 617900; Herpes simplex virus 1 encephalitis; Defects in Intrinsic and Innate Immunity to {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8}, OMIM:617900; Autoinflammation with arthritis and vasculitis, OMIM:620880
Primary immunodeficiency or monogenic inflammatory bowel disease v8.15 TBK1 Achchuthan Shanmugasundram Publications for gene: TBK1 were set to 22851595; 26513235
Primary immunodeficiency or monogenic inflammatory bowel disease v8.14 TBK1 Achchuthan Shanmugasundram Tag Q2_25_ MOI tag was added to gene: TBK1.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.14 TBK1 Achchuthan Shanmugasundram reviewed gene: TBK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34363755; Phenotypes: {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8}, OMIM:617900, Autoinflammation with arthritis and vasculitis, OMIM:620880; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Autoinflammatory disorders v2.24 TBK1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Dorota Rowczenio, there is sufficient evidence available (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Autoinflammatory disorders v2.24 TBK1 Achchuthan Shanmugasundram changed review comment from: PMID:34363755 reported the identification of homozygous loss-of-function variants in TBK1 gene in four patients from three unrelated families. All of them presented with chronic and systemic autoinflammation, but not severe viral infections. Supporting functional evidence is also available.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620880).; to: PMID:34363755 reported the identification of three different homozygous loss-of-function variants in TBK1 gene in four patients from three unrelated families. All of them presented with chronic and systemic autoinflammation, but not severe viral infections. Supporting functional evidence is also available.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620880).
Autoinflammatory disorders v2.24 TBK1 Achchuthan Shanmugasundram Classified gene: TBK1 as Amber List (moderate evidence)
Autoinflammatory disorders v2.24 TBK1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated families and functional evidence) for the association of biallelic TBK1 variants with autoinflammatory disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Autoinflammatory disorders v2.24 TBK1 Achchuthan Shanmugasundram Gene: tbk1 has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.23 TBK1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: TBK1.
Tag Q2_25_ NHS_review tag was added to gene: TBK1.
Autoinflammatory disorders v2.23 TBK1 Achchuthan Shanmugasundram Phenotypes for gene: TBK1 were changed from chronic and systemic autoinflammation driven by TNF-induced cell death to Autoinflammation with arthritis and vasculitis, OMIM:620880
Autoinflammatory disorders v2.22 TBK1 Achchuthan Shanmugasundram Publications for gene: TBK1 were set to PMID: 34363755; PMID: 34210994; PMID: 28148298; PMID: 34363755
Autoinflammatory disorders v2.21 TBK1 Achchuthan Shanmugasundram reviewed gene: TBK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34363755; Phenotypes: Autoinflammation with arthritis and vasculitis, OMIM:620880; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory disorders v2.21 RELA Arina Puzriakova Phenotypes for gene: RELA were changed from Autoinflammatory disease, familial, behcet-like 3 to Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287
Autoinflammatory disorders v2.20 POMP Arina Puzriakova Classified gene: POMP as Amber List (moderate evidence)
Autoinflammatory disorders v2.20 POMP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least 4 unrelated cases with neonatal onset inflammatory disease and heterozygous LOF variants in the POMP gene (PMID: 26524591; 29805043; 38111302)
Autoinflammatory disorders v2.20 POMP Arina Puzriakova Gene: pomp has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.19 POMP Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: POMP.
Tag Q2_25_ NHS_review tag was added to gene: POMP.
Autoinflammatory disorders v2.19 POMP Arina Puzriakova Publications for gene: POMP were set to PMID: 38111302; PMID: 29805043
Palmoplantar keratoderma and erythrokeratodermas v1.32 POMP Arina Puzriakova Classified gene: POMP as Green List (high evidence)
Palmoplantar keratoderma and erythrokeratodermas v1.32 POMP Arina Puzriakova Added comment: Comment on list classification: Promoting from Red to Green to match the latest rating on the GMS panels (R165/R166)
Palmoplantar keratoderma and erythrokeratodermas v1.32 POMP Arina Puzriakova Gene: pomp has been classified as Green List (High Evidence).
Autoinflammatory disorders v2.18 POMP Arina Puzriakova Phenotypes for gene: POMP were changed from Proteasome-associated autoinflammatory syndrome 2 to Proteasome-associated autoinflammatory syndrome 2, OMIM:618048
Autoinflammatory disorders v2.17 IKBKG Arina Puzriakova Publications for gene: IKBKG were set to PMID: 35289316
Autoinflammatory disorders v2.16 IKBKG Arina Puzriakova Classified gene: IKBKG as Amber List (moderate evidence)
Autoinflammatory disorders v2.16 IKBKG Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Variants in the IKBKG gene (also known as NEMO) can be linked to a autoinflammatory disorder characterised by the onset of systemic autoinflammation in the first months of life. Clinical manifestations are variable but include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. At least 9 unrelated cases have been reported, including two females (PMID: 31874111; 35120036; 35289316; 39264518).
Autoinflammatory disorders v2.16 IKBKG Arina Puzriakova Gene: ikbkg has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.15 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Autoinflammatory disease, systemic, X-linked to Autoinflammatory disease, systemic, X-linked, OMIM:301081
Autoinflammatory disorders v2.14 IKBKG Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: IKBKG.
Tag Q2_25_ NHS_review tag was added to gene: IKBKG.
Renal tubulopathies v5.5 OCRL Arina Puzriakova Phenotypes for gene: OCRL were changed from Dent disease 2, 300555. Lowe syndrome, 309000 to Dent disease 2, OMIM:300555
Renal tubulopathies v5.4 CLCN5 Arina Puzriakova Phenotypes for gene: CLCN5 were changed from Dent disease, 300009. Hypophosphatemic rickets, 300554. Nephrolithiasis, type I, 310468. Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis, 308990 to Dent disease 1, OMIM:300009
Renal tubulopathies v5.3 OCRL Arina Puzriakova changed review comment from: Comment on list classification: Upgrading from Red to Amber but this gene should be promoted to Green at the next GMS panel update, in line with the review by Beccy Cummings (NHS).

Variants in the CLCN5 gene cause Dent disease, a disorder of proximal renal tubular dysfunction, which could plausibly be picked up via this panel and therefore warrants inclusion.; to: Comment on list classification: Upgrading from Red to Amber but this gene should be promoted to Green at the next GMS panel update, in line with the review by Beccy Cummings (NHS).

Variants in the OCRL gene cause Dent disease, a disorder of proximal renal tubular dysfunction, which could plausibly be picked up via this panel and therefore warrants inclusion.
Renal tubulopathies v5.3 OCRL Arina Puzriakova Classified gene: OCRL as Amber List (moderate evidence)
Renal tubulopathies v5.3 OCRL Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber but this gene should be promoted to Green at the next GMS panel update, in line with the review by Beccy Cummings (NHS).

Variants in the CLCN5 gene cause Dent disease, a disorder of proximal renal tubular dysfunction, which could plausibly be picked up via this panel and therefore warrants inclusion.
Renal tubulopathies v5.3 OCRL Arina Puzriakova Gene: ocrl has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v5.2 OCRL Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: OCRL.
Tag Q2_25_ NHS_review tag was added to gene: OCRL.
Renal tubulopathies v5.2 CLCN5 Arina Puzriakova Classified gene: CLCN5 as Amber List (moderate evidence)
Renal tubulopathies v5.2 CLCN5 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber but this gene should be promoted to Green at the next GMS panel update, in line with the review by Beccy Cummings (NHS).

Variants in the CLCN5 gene cause Dent disease, a disorder of proximal renal tubular dysfunction, which could plausibly be picked up via this panel and therefore warrants inclusion.
Renal tubulopathies v5.2 CLCN5 Arina Puzriakova Gene: clcn5 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v5.1 CLCN5 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: CLCN5.
Tag Q2_25_ NHS_review tag was added to gene: CLCN5.
Intellectual disability v9.24 CLCN5 Arina Puzriakova Mode of inheritance for gene: CLCN5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.14 ELF4 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous ELF4 variants and autoinflammatory disorder, the MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next GMS update.; to: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous ELF4 variants and autoinflammatory disorder, the MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next GMS update.

The 'Skewed X-inactivation' tag has also been added as skewed X chromosome inactivation patterns were observed in all three female patients in the same publication.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.14 ELF4 Achchuthan Shanmugasundram Tag Skewed X-inactivation tag was added to gene: ELF4.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.14 ELF4 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous ELF4 variants and autoinflammatory disorder, the MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.14 ELF4 Achchuthan Shanmugasundram Mode of inheritance for gene: ELF4 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency or monogenic inflammatory bowel disease v8.13 ELF4 Achchuthan Shanmugasundram Phenotypes for gene: ELF4 were changed from Inflammatory bowel disease; Mucosal inflammation; Fever; Ulcers; Behcet-like disease; X-linked hypogammaglobulinemia with isolated growth hormone deficiency to Autoinflammatory syndrome, familial, X-linked, Behcet-like 2, OMIM:301074
Primary immunodeficiency or monogenic inflammatory bowel disease v8.12 ELF4 Achchuthan Shanmugasundram Publications for gene: ELF4 were set to 16264330; 34326534
Primary immunodeficiency or monogenic inflammatory bowel disease v8.11 ELF4 Achchuthan Shanmugasundram Tag Q2_25_ MOI tag was added to gene: ELF4.
Tag Q2_25_expert_review tag was added to gene: ELF4.
Autoinflammatory disorders v2.14 ELF4 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for this gene-disease association and hence this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Dorota Rowczenio, there is sufficient evidence available for this gene-disease association. Hence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.11 ELF4 Achchuthan Shanmugasundram reviewed gene: ELF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 34326534, 35266071, 36823308, 38231408, 38773005, 39563044, 39976696; Phenotypes: Autoinflammatory syndrome, familial, X-linked, Behcet-like 2, OMIM:301074; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Autoinflammatory disorders v2.14 ELF4 Achchuthan Shanmugasundram Classified gene: ELF4 as Amber List (moderate evidence)
Autoinflammatory disorders v2.14 ELF4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for this gene-disease association and hence this gene can be promoted to green rating in the next GMS update.
Autoinflammatory disorders v2.14 ELF4 Achchuthan Shanmugasundram Gene: elf4 has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.13 ELF4 Achchuthan Shanmugasundram Phenotypes for gene: ELF4 were changed from Autoinflammatory syndrome, familial, X-linked, Behcet-like 2 to Autoinflammatory syndrome, familial, X-linked, Behcet-like 2, OMIM:301074
Autoinflammatory disorders v2.12 ELF4 Achchuthan Shanmugasundram Publications for gene: ELF4 were set to PMID: 35266071; PMID: 34326534; PMID: 39976696; PMID: 39563044; PMID: 38773005; PMID: 38231408; PMID: 36823308
Autoinflammatory disorders v2.11 ELF4 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous variants and autoinflammatory disorder, the MOI has been set as 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)'.

The 'skewed X-inactivation' tag has also been added.; to: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous ELF4 variants and autoinflammatory disorder in PMID:39976696, the MOI has been set as 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)'.

The 'Skewed X-inactivation' tag has also been added as skewed X chromosome inactivation patterns were observed in all three female patients in the same publication.
Autoinflammatory disorders v2.11 ELF4 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous variants and autoinflammatory disorder, the MOI has been set as 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)'.

The 'skewed X-inactivation' tag has also been added.
Autoinflammatory disorders v2.11 ELF4 Achchuthan Shanmugasundram Mode of inheritance for gene: ELF4 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Autoinflammatory disorders v2.10 ELF4 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: ELF4.
Tag Q2_25_ NHS_review tag was added to gene: ELF4.
Autoinflammatory disorders v2.10 ELF4 Achchuthan Shanmugasundram Tag Skewed X-inactivation tag was added to gene: ELF4.
Autoinflammatory disorders v2.10 ELF4 Achchuthan Shanmugasundram edited their review of gene: ELF4: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Autoinflammatory disorders v2.10 ELF4 Achchuthan Shanmugasundram edited their review of gene: ELF4: Added comment: PMID:34326534 - Two variants identified in three unrelated males with autoinflammatory disease characterised by fever, oral ulcers and mucosal inflammation. Supported by functional studies and mouse model.

PMID:35266071 - Paediatric male patient identified with a hemizygous variant and was suffering from recurrent viral and bacterial respiratory infection, refractory oral ulcer, constipation, and arthritis. Supported by functional studies and mouse model.

PMID:36823308 - Five more male patients presenting mainly with oral ulcer, inflammatory bowel disease-like symptoms, fever of unknown origin, anaemia, or systemic lupus erythematosus.

PMID:38231408 - An international cohort of fourteen patients exhibiting a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anaemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum.

PMID:38773005 - A 11-year-old boy presented with a Behcet's-like phenotype including elevated inflammatory indicators, ileocecal ulcers and inflammatory cell infiltrations. The patient was treated with long-term immunosuppressant and TNF-alpha blocker. Supporting functional studies available.

PMID:39563044 - Two male patients presented with recurrent oral ulcers and abdominal pain and had significant increase in inflammatory markers, multiple intestinal ulcers, and both patients developed intestinal fistulas.

PMID:39976696 - Three unrelated paediatric female patients, who are all heterozygous for ELF4 variants. Similar to reported male patients, the main clinical features include recurring oral ulcers, abdominal pain and diarrhoea with colonoscopy showing ulcers in the colon. Skewed X chromosome inactivation patterns were observed in all three female patients, with over-inactivation of the X chromosome carrying the wild-type allele confirmed in two of them.; Changed publications to: 34326534, 35266071, 36823308, 38231408, 38773005, 39563044, 39976696
Autoinflammatory disorders v2.10 ELF4 Achchuthan Shanmugasundram reviewed gene: ELF4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory syndrome, familial, X-linked, Behcet-like 2, OMIM:301074; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Autoinflammatory disorders v2.10 COPA Achchuthan Shanmugasundram Tag Q2_25_ NHS_review tag was added to gene: COPA.
Autoinflammatory disorders v2.10 ALPK1 Achchuthan Shanmugasundram Tag Q2_25_ NHS_review tag was added to gene: ALPK1.
Autoinflammatory disorders v2.10 ALPK1 Achchuthan Shanmugasundram Classified gene: ALPK1 as Amber List (moderate evidence)
Autoinflammatory disorders v2.10 ALPK1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dorota Rowczenio, there is sufficient evidence available for the association of ALPK1 with an auto-inflammatory condition, ROSAH. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Autoinflammatory disorders v2.10 ALPK1 Achchuthan Shanmugasundram Gene: alpk1 has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.9 ALPK1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: ALPK1.
Autoinflammatory disorders v2.9 ALPK1 Achchuthan Shanmugasundram Phenotypes for gene: ALPK1 were changed from Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis, and migraine Headache syndrome (ROSAH) to ROSAH syndrome, OMIM:614979
Autoinflammatory disorders v2.8 ALPK1 Achchuthan Shanmugasundram Publications for gene: ALPK1 were set to PMID: 30967659; PMID: 36332842; PMID: 38251500; PMID: 40069099; PMID: 35868845
Autoinflammatory disorders v2.7 ALPK1 Achchuthan Shanmugasundram Mode of pathogenicity for gene: ALPK1 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
GI tract tumours v1.26 MBD4 Arina Puzriakova Classified gene: MBD4 as Green List (high evidence)
GI tract tumours v1.26 MBD4 Arina Puzriakova Gene: mbd4 has been classified as Green List (High Evidence).
Autoinflammatory disorders v2.6 ALPK1 Achchuthan Shanmugasundram changed review comment from: This gene has been associated with ROSAH syndrome (MIM #614979) in OMIM. There is sufficient evidence available (>30 unrelated families) in support of this gene-disease association.

Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis, AA amyloidosis and intraocular inflammation.

In vitro assays and systematic analysis of inflammatory features also established ROSAH as an autoinflammatory disease.

This gene has already been promoted to green rating on R15 Primary immunodeficiency or monogenic inflammatory bowel disease panel (https://panelapp.genomicsengland.co.uk/panels/398/gene/ALPK1/). It is also green on Autoinflammatory Disorders panel from PanelApp Australia - https://panelapp-aus.org/panels/238/gene/ALPK1/.; to: This gene has been associated with ROSAH syndrome (MIM #614979) in OMIM. There is sufficient evidence available (>30 unrelated families) in support of this gene-disease association.

Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis, AA amyloidosis and intraocular inflammation.

In vitro assays and systematic analysis of inflammatory features also established ROSAH as an autoinflammatory disease.

Gain-of-function missense variants in ALPK1 were reported to cause ROSAH in PMID:35868845.

This gene has already been promoted to green rating on R15 Primary immunodeficiency or monogenic inflammatory bowel disease panel (https://panelapp.genomicsengland.co.uk/panels/398/gene/ALPK1/). It is also green on Autoinflammatory Disorders panel from PanelApp Australia - https://panelapp-aus.org/panels/238/gene/ALPK1/.
GI tract tumours v1.25 MBD4 Arina Puzriakova Classified gene: MBD4 as Amber List (moderate evidence)
GI tract tumours v1.25 MBD4 Arina Puzriakova Added comment: Comment on list classification: This gene was reviewed by the cancer expert group and the evidence was determined as sufficient for inclusion on this panel. Therefore, upgrading from Amber to Green.
GI tract tumours v1.25 MBD4 Arina Puzriakova Gene: mbd4 has been classified as Amber List (Moderate Evidence).
GI tract tumours v1.24 MBD4 Arina Puzriakova Publications for gene: MBD4 were set to 12417741; 30049810; 32239153; 35460607
GI tract tumours v1.23 MBD4 Arina Puzriakova Phenotypes for gene: MBD4 were changed from Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma to Tumor predisposition syndrome 2, OMIM:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
Inherited predisposition to acute myeloid leukaemia (AML) v3.4 MBD4 Arina Puzriakova Phenotypes for gene: MBD4 were changed from Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma to Tumor predisposition syndrome 2, OMIM:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
Haematological malignancies cancer susceptibility v4.25 MBD4 Arina Puzriakova Phenotypes for gene: MBD4 were changed from Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma to Tumor predisposition syndrome 2, OMIM:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
Inherited polyposis and early onset colorectal cancer - germline testing v3.5 MBD4 Arina Puzriakova Phenotypes for gene: MBD4 were changed from Tumor predisposition syndrome 2:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma to Tumor predisposition syndrome 2, OMIM:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
Inherited polyposis and early onset colorectal cancer - germline testing v3.4 MBD4 Arina Puzriakova Phenotypes for gene: MBD4 were changed from Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma to Tumor predisposition syndrome 2:619975; Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma
Inherited polyposis and early onset colorectal cancer - germline testing v3.3 MBD4 Arina Puzriakova Publications for gene: MBD4 were set to 12417741; 30049810; 32239153; 35460607
Inherited polyposis and early onset colorectal cancer - germline testing v3.2 MBD4 Arina Puzriakova Classified gene: MBD4 as Amber List (moderate evidence)
Inherited polyposis and early onset colorectal cancer - germline testing v3.2 MBD4 Arina Puzriakova Added comment: Comment on list classification: This gene was reviewed by the cancer expert group and the evidence was determined as sufficient for inclusion on this panel. Therefore, submitting again as it should be updated to Green at the next GMS panel update.

This gene is also now green on the R347 signed-off panel (v3.0).
Inherited polyposis and early onset colorectal cancer - germline testing v3.2 MBD4 Arina Puzriakova Gene: mbd4 has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.6 ALPK1 Achchuthan Shanmugasundram commented on gene: ALPK1: This gene has been associated with ROSAH syndrome (MIM #614979) in OMIM. There is sufficient evidence available (>30 unrelated families) in support of this gene-disease association.

Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis, AA amyloidosis and intraocular inflammation.

In vitro assays and systematic analysis of inflammatory features also established ROSAH as an autoinflammatory disease.

This gene has already been promoted to green rating on R15 Primary immunodeficiency or monogenic inflammatory bowel disease panel (https://panelapp.genomicsengland.co.uk/panels/398/gene/ALPK1/). It is also green on Autoinflammatory Disorders panel from PanelApp Australia - https://panelapp-aus.org/panels/238/gene/ALPK1/.
Inherited polyposis and early onset colorectal cancer - germline testing v3.1 MBD4 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: MBD4.
Tag Q2_25_ NHS_review tag was added to gene: MBD4.
Familial tumours of the nervous system v2.3 CDKN2A Arina Puzriakova Classified gene: CDKN2A as Amber List (moderate evidence)
Familial tumours of the nervous system v2.3 CDKN2A Arina Puzriakova Added comment: Comment on list classification: This gene was reviewed by the cancer expert group and the evidence was determined as sufficient for inclusion on this panel. Therefore, it should be updated to Green at the next GMS panel update.

Melanoma and neural system tumor syndrome (OMIM:155755) associated with heterozygous variants in the CDKN2A gene is characterised by a dual predisposition to melanoma and neural system tumors, commonly astrocytoma.
Familial tumours of the nervous system v2.3 CDKN2A Arina Puzriakova Gene: cdkn2a has been classified as Amber List (Moderate Evidence).
Familial tumours of the nervous system v2.2 CDKN2A Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: CDKN2A.
Tag Q2_25_ NHS_review tag was added to gene: CDKN2A.
Familial tumours of the nervous system v2.2 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from MELANOMA; PANCREATIC CANCER; ASTROCYTOMA; GLIOBLASTOMA; SCHWANNOMA; NEUROFIBROMA; MENINGIOMA; MALIGNANT PERIPHERAL NERVE SHEATH TUMOURS to {Melanoma and neural system tumor syndrome}, OMIM:155755; MELANOMA; PANCREATIC CANCER; ASTROCYTOMA; GLIOBLASTOMA; SCHWANNOMA; NEUROFIBROMA; MENINGIOMA; MALIGNANT PERIPHERAL NERVE SHEATH TUMOURS
Autoinflammatory disorders v2.6 ALPK1 Achchuthan Shanmugasundram Source Literature was added to ALPK1.
Autoinflammatory disorders v2.5 ALPK1 Achchuthan Shanmugasundram reviewed gene: ALPK1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 30967659, 35868845, 36332842, 38251500, 40069099; Phenotypes: ROSAH syndrome, OMIM:614979; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited breast cancer and ovarian cancer v2.15 BARD1 Arina Puzriakova Publications for gene: BARD1 were set to 33471991; 37592023; 15342711
Inherited ovarian cancer (without breast cancer) v4.6 BARD1 Arina Puzriakova Phenotypes for gene: BARD1 were changed from {Breast cancer, susceptibility to}, 114480; Breast Cancer to {Breast cancer, susceptibility to}, OMIM:114480
Inherited ovarian cancer (without breast cancer) v4.5 BARD1 Arina Puzriakova Mode of inheritance for gene: BARD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial breast cancer v1.24 BARD1 Arina Puzriakova Publications for gene: BARD1 were set to
Familial breast cancer v1.23 BARD1 Arina Puzriakova Classified gene: BARD1 as Green List (high evidence)
Familial breast cancer v1.23 BARD1 Arina Puzriakova Added comment: Comment on list classification: This gene was reviewed by the cancer expert group and the evidence was determined as sufficient for inclusion on breast cancer panels. Therefore, upgrading from Red to Green.
Familial breast cancer v1.23 BARD1 Arina Puzriakova Gene: bard1 has been classified as Green List (High Evidence).
Familial breast cancer v1.22 BARD1 Arina Puzriakova Mode of inheritance for gene: BARD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited breast cancer and ovarian cancer v2.14 BARD1 Arina Puzriakova Classified gene: BARD1 as Amber List (moderate evidence)
Inherited breast cancer and ovarian cancer v2.14 BARD1 Arina Puzriakova Added comment: Comment on list classification: This gene was reviewed by the cancer expert group and the evidence was determined as sufficient for inclusion on this panel. Therefore, it should be updated to Green at the next GMS panel update.
Inherited breast cancer and ovarian cancer v2.14 BARD1 Arina Puzriakova Gene: bard1 has been classified as Amber List (Moderate Evidence).
Inherited breast cancer and ovarian cancer v2.13 BARD1 Arina Puzriakova commented on gene: BARD1
Inherited breast cancer and ovarian cancer v2.13 BARD1 Arina Puzriakova Publications for gene: BARD1 were set to PMID: 33471991
Familial breast cancer v1.21 BARD1 Arina Puzriakova Phenotypes for gene: BARD1 were changed from {Breast cancer, susceptibility to}, 114480; Breast Cancer to {Breast cancer, susceptibility to}, OMIM:114480
Inherited breast cancer and ovarian cancer v2.12 BARD1 Arina Puzriakova Phenotypes for gene: BARD1 were changed from breast cancer to {Breast cancer, susceptibility to}, OMIM:114480
Inherited breast cancer and ovarian cancer v2.11 BARD1 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: BARD1.
Tag Q2_25_ NHS_review tag was added to gene: BARD1.
Respiratory ciliopathies including non-CF bronchiectasis v4.2 CCDC65 Arina Puzriakova Publications for gene: CCDC65 were set to
Respiratory ciliopathies including non-CF bronchiectasis v4.1 CCDC65 Arina Puzriakova Tag founder-effect tag was added to gene: CCDC65.
Undiagnosed metabolic disorders v1.629 USF1 Achchuthan Shanmugasundram Tag Q1_25_ demote_amber was removed from gene: USF1.
Tag Q1_25_ NHS_review was removed from gene: USF1.
Tag Q1_25_ MOI was removed from gene: USF1.
Tag Q1_25_ promote_green was removed from gene: USF1.
Tag Q1_25_ demote_red was removed from gene: USF1.
Tag Q1_25_ expert_review was removed from gene: USF1.
Tag Q1_25_ phenotype was removed from gene: USF1.
Cerebral vascular malformations v4.4 ANO1 Eleanor Williams commented on gene: ANO1
Likely inborn error of metabolism v8.54 TEFM Achchuthan Shanmugasundram Classified gene: TEFM as Amber List (moderate evidence)
Likely inborn error of metabolism v8.54 TEFM Achchuthan Shanmugasundram Added comment: Comment on list classification: TEFM has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/TEFM/) as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.54 TEFM Achchuthan Shanmugasundram Gene: tefm has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.53 TEFM Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: TEFM.
Likely inborn error of metabolism v8.53 TEFM Achchuthan Shanmugasundram Classified gene: TEFM as Amber List (moderate evidence)
Likely inborn error of metabolism v8.53 TEFM Achchuthan Shanmugasundram Gene: tefm has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.52 TEFM Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
Likely inborn error of metabolism v8.52 TEFM Achchuthan Shanmugasundram gene: TEFM was added
gene: TEFM was added to Likely inborn error of metabolism. Sources: Expert Review Green,NHS GMS,Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Combined oxidative phosphorylation deficiency 58, OMIM:620451
Likely inborn error of metabolism v8.51 TAMM41 Achchuthan Shanmugasundram Classified gene: TAMM41 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.51 TAMM41 Achchuthan Shanmugasundram Added comment: Comment on list classification: TAMM41 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/TAMM41/) as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.51 TAMM41 Achchuthan Shanmugasundram Gene: tamm41 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.50 TAMM41 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: TAMM41.
Likely inborn error of metabolism v8.50 TAMM41 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
Likely inborn error of metabolism v8.50 TAMM41 Achchuthan Shanmugasundram gene: TAMM41 was added
gene: TAMM41 was added to Likely inborn error of metabolism. Sources: NHS GMS,Literature,Expert Review Green
Mode of inheritance for gene: TAMM41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAMM41 were set to 35321494
Phenotypes for gene: TAMM41 were set to Combined oxidative phosphorylation deficiency 56, OMIM:620139
Likely inborn error of metabolism v8.49 SUPV3L1 Achchuthan Shanmugasundram reviewed gene: SUPV3L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.49 SUPV3L1 Achchuthan Shanmugasundram Tag Q1_25_ promote_green was removed from gene: SUPV3L1.
Tag Q2_25_ promote_green tag was added to gene: SUPV3L1.
Likely inborn error of metabolism v8.49 SUPV3L1 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
Likely inborn error of metabolism v8.49 SUPV3L1 Achchuthan Shanmugasundram gene: SUPV3L1 was added
gene: SUPV3L1 was added to Likely inborn error of metabolism. Sources: Literature,Expert Review Amber
Q1_25_ promote_green tags were added to gene: SUPV3L1.
Mode of inheritance for gene: SUPV3L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUPV3L1 were set to 35023579; 39596606
Phenotypes for gene: SUPV3L1 were set to Mitochondrial RNA Helicase SUPV3L1-Associated neurodegenerative syndrome
Likely inborn error of metabolism v8.48 SPATA5 Achchuthan Shanmugasundram Classified gene: SPATA5 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.48 SPATA5 Achchuthan Shanmugasundram Added comment: Comment on list classification: SPATA5 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/SPATA5/) as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.48 SPATA5 Achchuthan Shanmugasundram Gene: spata5 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.47 SPATA5 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SPATA5.
Likely inborn error of metabolism v8.47 SPATA5 Achchuthan Shanmugasundram reviewed gene: SPATA5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.47 SPATA5 Achchuthan Shanmugasundram Deleted their review
Likely inborn error of metabolism v8.47 SPATA5 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
Likely inborn error of metabolism v8.47 SPATA5 Achchuthan Shanmugasundram gene: SPATA5 was added
gene: SPATA5 was added to Likely inborn error of metabolism. Sources: Expert Review Green,NHS GMS,Literature
new-gene-name tags were added to gene: SPATA5.
Mode of inheritance for gene: SPATA5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA5 were set to 27246907; 29343804; 26299366; 28293831; 30009132; 36849973
Phenotypes for gene: SPATA5 were set to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, OMIM:616577
Penetrance for gene: SPATA5 were set to Complete
Likely inborn error of metabolism v8.46 SLC25A36 Achchuthan Shanmugasundram Classified gene: SLC25A36 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.46 SLC25A36 Achchuthan Shanmugasundram Added comment: Comment on list classification: SLC25A36 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/SLC25A36/) as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.46 SLC25A36 Achchuthan Shanmugasundram Gene: slc25a36 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.45 SLC25A36 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SLC25A36.
Likely inborn error of metabolism v8.45 SLC25A36 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
Likely inborn error of metabolism v8.45 SLC25A36 Achchuthan Shanmugasundram gene: SLC25A36 was added
gene: SLC25A36 was added to Likely inborn error of metabolism. Sources: NHS GMS,Expert Review Green,Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34576089; 34971397; 36695547
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8, OMIM:620211
Likely inborn error of metabolism v8.44 SLC25A24 Achchuthan Shanmugasundram Classified gene: SLC25A24 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.44 SLC25A24 Achchuthan Shanmugasundram Added comment: Comment on list classification: SLC25A24 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/SLC25A24/) as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.44 SLC25A24 Achchuthan Shanmugasundram Gene: slc25a24 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.43 SLC25A24 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SLC25A24.
Likely inborn error of metabolism v8.43 SLC25A24 Achchuthan Shanmugasundram reviewed gene: SLC25A24: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v8.43 SLC25A24 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.19
Likely inborn error of metabolism v8.43 SLC25A24 Achchuthan Shanmugasundram gene: SLC25A24 was added
gene: SLC25A24 was added to Likely inborn error of metabolism. Sources: Expert list,NHS GMS,Expert Review Green
Mode of inheritance for gene: SLC25A24 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC25A24 were set to 29903433; 29100093; 29100094
Phenotypes for gene: SLC25A24 were set to Fontaine progeroid syndrome, OMIM:612289; Fontaine progeroid syndrome, MONDO:0012853
Mitochondrial disorders v9.19 SLC25A24 Achchuthan Shanmugasundram Phenotypes for gene: SLC25A24 were changed from Fontaine progeroid syndrome, OMIM; 612289; Fontaine progeroid syndrome, MONDO:0012853 to Fontaine progeroid syndrome, OMIM:612289; Fontaine progeroid syndrome, MONDO:0012853
Likely inborn error of metabolism v8.42 QARS Achchuthan Shanmugasundram Classified gene: QARS as Amber List (moderate evidence)
Likely inborn error of metabolism v8.42 QARS Achchuthan Shanmugasundram Added comment: Comment on list classification: QARS has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/QARS/). Hence, this gene can also be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.42 QARS Achchuthan Shanmugasundram Gene: qars has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.41 QARS Achchuthan Shanmugasundram Phenotypes for gene: QARS were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis) to Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, OMIM:615760
Likely inborn error of metabolism v8.40 QARS Achchuthan Shanmugasundram Publications for gene: QARS were set to 28620870; 25471517; 25432320; 25041233; 24656866
Likely inborn error of metabolism v8.39 QARS Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: QARS.
Likely inborn error of metabolism v8.39 QARS Achchuthan Shanmugasundram reviewed gene: QARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32042906; Phenotypes: Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, OMIM:615760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.39 POLRMT Achchuthan Shanmugasundram Classified gene: POLRMT as Amber List (moderate evidence)
Likely inborn error of metabolism v8.39 POLRMT Achchuthan Shanmugasundram Added comment: Comment on list classification: POLRMT has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/POLRMT/) as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.39 POLRMT Achchuthan Shanmugasundram Gene: polrmt has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.38 POLRMT Achchuthan Shanmugasundram reviewed gene: POLRMT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v8.38 POLRMT Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: POLRMT.
Likely inborn error of metabolism v8.38 POLRMT Achchuthan Shanmugasundram Deleted their review
Likely inborn error of metabolism v8.38 POLRMT Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.18
Likely inborn error of metabolism v8.38 POLRMT Achchuthan Shanmugasundram gene: POLRMT was added
gene: POLRMT was added to Likely inborn error of metabolism. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: POLRMT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POLRMT were set to 24386581; 33602924
Phenotypes for gene: POLRMT were set to Combined oxidative phosphorylation deficiency 55, OMIM:619743
Likely inborn error of metabolism v8.37 PITRM1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene has already been promoted to green rating on the Mitochondrial disorder panel. Hence, this gene can be promoted to green rating on this panel in the next GMS update.; to: Comment on list classification: This gene has already been promoted to green rating on the Mitochondrial disorders panel. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.37 PITRM1 Achchuthan Shanmugasundram Phenotypes for gene: PITRM1 were changed from Spinocerebellar ataxia, autosomal recessive 30, OMIM:61940 to Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405
Likely inborn error of metabolism v8.36 PITRM1 Achchuthan Shanmugasundram Classified gene: PITRM1 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.36 PITRM1 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has already been promoted to green rating on the Mitochondrial disorder panel. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.36 PITRM1 Achchuthan Shanmugasundram Gene: pitrm1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.35 PITRM1 Achchuthan Shanmugasundram Phenotypes for gene: PITRM1 were changed from mental retardation, spinocerebellar ataxia, cognitive decline and psychosis to Spinocerebellar ataxia, autosomal recessive 30, OMIM:61940
Likely inborn error of metabolism v8.34 PITRM1 Achchuthan Shanmugasundram commented on gene: PITRM1: Zornitza Stark (Australian Genomics) reviewed on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/PITRM1/) that three families were reported with two unique variants, and mitochondrial dysfunction was identified in in vitro functional assays and mouse model.
Likely inborn error of metabolism v8.34 PITRM1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: PITRM1.
Likely inborn error of metabolism v8.34 PITRM1 Achchuthan Shanmugasundram reviewed gene: PITRM1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v9.18 PITRM1 Achchuthan Shanmugasundram Phenotypes for gene: PITRM1 were changed from mental retardation, spinocerebellar ataxia, cognitive decline and psychosis to Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405
Ataxia and cerebellar anomalies - narrow panel v8.4 PITRM1 Achchuthan Shanmugasundram Phenotypes for gene: PITRM1 were changed from Ataxia; Intellectual disability to Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405
Likely inborn error of metabolism v8.34 MRPL49 Achchuthan Shanmugasundram Classified gene: MRPL49 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.34 MRPL49 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of MRPL49 with combined oxidative phosphorylation deficiency phenotype.

This gene is currently being recommended for promotion to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/MRPL49/). Hence, this gene can also be considered for promotion to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.34 MRPL49 Achchuthan Shanmugasundram Gene: mrpl49 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.33 MRPL49 Achchuthan Shanmugasundram reviewed gene: MRPL49: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.33 MRPL49 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.17
Likely inborn error of metabolism v8.33 MRPL49 Achchuthan Shanmugasundram gene: MRPL49 was added
gene: MRPL49 was added to Likely inborn error of metabolism. Sources: Expert Review Amber,Literature
Q2_25_ promote_green tags were added to gene: MRPL49.
Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL49 were set to 40043708
Phenotypes for gene: MRPL49 were set to Combined oxidative phosphorylation deficiency 60, OMIM:621195; combined oxidative phosphorylation deficiency, MONDO:0000732
Likely inborn error of metabolism v8.32 MRPL39 Achchuthan Shanmugasundram Classified gene: MRPL39 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.32 MRPL39 Achchuthan Shanmugasundram Added comment: Comment on list classification: MRPL39 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/MRPL39/) as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.32 MRPL39 Achchuthan Shanmugasundram Gene: mrpl39 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.31 MRPL39 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: MRPL39.
Likely inborn error of metabolism v8.31 MRPL39 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.17
Likely inborn error of metabolism v8.31 MRPL39 Achchuthan Shanmugasundram gene: MRPL39 was added
gene: MRPL39 was added to Likely inborn error of metabolism. Sources: NHS GMS,Expert Review Green,Literature
Mode of inheritance for gene: MRPL39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL39 were set to 37133451
Phenotypes for gene: MRPL39 were set to Combined oxidative phosphorylation deficiency 59, OMIM:620646
Likely inborn error of metabolism v8.30 LIG3 Achchuthan Shanmugasundram Classified gene: LIG3 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.30 LIG3 Achchuthan Shanmugasundram Added comment: Comment on list classification: LIG3 has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/LIG3/).

As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.30 LIG3 Achchuthan Shanmugasundram Gene: lig3 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.29 LIG3 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: LIG3.
Likely inborn error of metabolism v8.29 LIG3 Achchuthan Shanmugasundram Phenotypes for gene: LIG3 were changed from gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion to Mitochondrial DNA depletion syndrome 20 (MNGIE type), OMIM:619780
Likely inborn error of metabolism v8.28 LIG3 Achchuthan Shanmugasundram Marked gene: LIG3 as ready
Likely inborn error of metabolism v8.28 LIG3 Achchuthan Shanmugasundram Gene: lig3 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v8.28 LIG3 Achchuthan Shanmugasundram reviewed gene: LIG3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 20 (MNGIE type), OMIM:619780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v9.17 LIG3 Achchuthan Shanmugasundram Phenotypes for gene: LIG3 were changed from gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion to Mitochondrial DNA depletion syndrome 20 (MNGIE type), OMIM:619780
White matter disorders and cerebral calcification - narrow panel v7.3 LIG3 Achchuthan Shanmugasundram Phenotypes for gene: LIG3 were changed from gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion to Mitochondrial DNA depletion syndrome 20 (MNGIE type), OMIM:619780
Likely inborn error of metabolism v8.28 LIG3 Achchuthan Shanmugasundram Entity copied from White matter disorders and cerebral calcification - narrow panel v7.2
Likely inborn error of metabolism v8.28 LIG3 Achchuthan Shanmugasundram gene: LIG3 was added
gene: LIG3 was added to Likely inborn error of metabolism. Sources: Expert Review Green,NHS GMS,Literature
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Likely inborn error of metabolism v8.27 KIAA0391 Achchuthan Shanmugasundram Classified gene: KIAA0391 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.27 KIAA0391 Achchuthan Shanmugasundram Added comment: Comment on list classification: KIAA0391 (PRORP) has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/KIAA0391/) as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.27 KIAA0391 Achchuthan Shanmugasundram Gene: kiaa0391 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.26 KIAA0391 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: KIAA0391.
Likely inborn error of metabolism v8.26 KIAA0391 Achchuthan Shanmugasundram reviewed gene: KIAA0391: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency 54, OMIM:619737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.26 KIAA0391 Achchuthan Shanmugasundram Deleted their review
Likely inborn error of metabolism v8.26 KIAA0391 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.16
Likely inborn error of metabolism v8.26 KIAA0391 Achchuthan Shanmugasundram gene: KIAA0391 was added
gene: KIAA0391 was added to Likely inborn error of metabolism. Sources: Literature,NHS GMS,Expert Review Green
new-gene-name tags were added to gene: KIAA0391.
Mode of inheritance for gene: KIAA0391 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0391 were set to 34715011
Phenotypes for gene: KIAA0391 were set to Combined oxidative phosphorylation deficiency 54, OMIM:619737
Mitochondrial disorders v9.16 KIAA0391 Achchuthan Shanmugasundram Phenotypes for gene: KIAA0391 were changed from Hearing loss, intellectual disability to Combined oxidative phosphorylation deficiency 54, OMIM:619737
Mitochondrial disorders v9.15 KIAA0391 Achchuthan Shanmugasundram edited their review of gene: KIAA0391: Changed phenotypes to: Combined oxidative phosphorylation deficiency 54, OMIM:619737; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.25 IDH3A Achchuthan Shanmugasundram Classified gene: IDH3A as Amber List (moderate evidence)
Likely inborn error of metabolism v8.25 IDH3A Achchuthan Shanmugasundram Added comment: Comment on list classification: IDH3A has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/IDH3A/) as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.25 IDH3A Achchuthan Shanmugasundram Gene: idh3a has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.24 HPDL Achchuthan Shanmugasundram changed review comment from: Comment on list classification: HPDL has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/HPDL/), as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association and HPDL is suggested to have a potential role in mitochondrial metabolism, this gene can be promoted to green rating in this panel in the next GMS update.; to: Comment on list classification: HPDL has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/HPDL/), as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association and HPDL is suggested to have a potential role in mitochondrial metabolism, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.24 IDH3A Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: IDH3A.
Likely inborn error of metabolism v8.24 IDH3A Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.15
Likely inborn error of metabolism v8.24 IDH3A Achchuthan Shanmugasundram gene: IDH3A was added
gene: IDH3A was added to Likely inborn error of metabolism. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: IDH3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IDH3A were set to 31012789; 30478029; 30058936; 28412069; 28058510
Phenotypes for gene: IDH3A were set to Retinitis pigmentosa 90, OMIM:619007; retinitis pigmentosa 90, MONDO:0033563
Likely inborn error of metabolism v8.23 HPDL Achchuthan Shanmugasundram changed review comment from: Comment on list classification: HPDL has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/HPDL/), as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association and HPDL is suggested to have a potential role in mitochondrial metabolism, this gene can be promoted to green rating in this panel in the next GMS update.; to: Comment on list classification: HPDL has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/HPDL/), as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the gene-disease association and HPDL is suggested to have a potential role in mitochondrial metabolism, this gene can be promoted to green rating in this panel in the next GMS update.
Likely inborn error of metabolism v8.23 HPDL Achchuthan Shanmugasundram Classified gene: HPDL as Amber List (moderate evidence)
Likely inborn error of metabolism v8.23 HPDL Achchuthan Shanmugasundram Added comment: Comment on list classification: HPDL has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/HPDL/), as detailed in the below reviews copied from that panel. As there is sufficient evidence available for the gene-disease association and HPDL is suggested to have a potential role in mitochondrial metabolism, this gene can be promoted to green rating in this panel in the next GMS update.
Likely inborn error of metabolism v8.23 HPDL Achchuthan Shanmugasundram Gene: hpdl has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.22 HPDL Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: HPDL.
Likely inborn error of metabolism v8.22 HPDL Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.15
Likely inborn error of metabolism v8.22 HPDL Achchuthan Shanmugasundram gene: HPDL was added
gene: HPDL was added to Likely inborn error of metabolism. Sources: Literature,NHS GMS,Expert Review Green
gene-checked tags were added to gene: HPDL.
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to 32707086
Phenotypes for gene: HPDL were set to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities OMIM:619026; Spastic paraplegia 83, autosomal recessive OMIM:619027
Likely inborn error of metabolism v8.21 CYCS Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: CYCS.
Likely inborn error of metabolism v8.21 CYCS Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are sufficient unrelated cases available to support a gene-disease association for CYCS. CYCS is located in the mitochondria and is involved in the electron transport system that functions in oxidative phosphorylation. In vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain.

This gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/CYCS/) and can therefore be promoted to green rating in the next GMS update.; to: Comment on list classification: There are sufficient unrelated cases available to support a gene-disease association for CYCS. CYCS is located in the mitochondria and is involved in the electron transport system that functions in oxidative phosphorylation. In vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain.

This gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/CYCS/) and can therefore be promoted to green rating in this panel in the next GMS update.
Likely inborn error of metabolism v8.21 CYCS Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are sufficient unrelated cases available to support a gene-disease association for CYCS. CYCS is located in the mitochondria and is involved in the electron transport system that functions in oxidative phosphorylation. In vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain.

This gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/CYCS/). This gene can therefore be promoted to green rating in the next GMS update.; to: Comment on list classification: There are sufficient unrelated cases available to support a gene-disease association for CYCS. CYCS is located in the mitochondria and is involved in the electron transport system that functions in oxidative phosphorylation. In vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain.

This gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/CYCS/) and can therefore be promoted to green rating in the next GMS update.
Likely inborn error of metabolism v8.21 CYCS Achchuthan Shanmugasundram Classified gene: CYCS as Amber List (moderate evidence)
Likely inborn error of metabolism v8.21 CYCS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are sufficient unrelated cases available to support a gene-disease association for CYCS. CYCS is located in the mitochondria and is involved in the electron transport system that functions in oxidative phosphorylation. In vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain.

This gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/CYCS/). This gene can therefore be promoted to green rating in the next GMS update.
Likely inborn error of metabolism v8.21 CYCS Achchuthan Shanmugasundram Gene: cycs has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.20 CYCS Achchuthan Shanmugasundram Publications for gene: CYCS were set to 24326104; PMID: 18345000
Likely inborn error of metabolism v8.19 CYCS Achchuthan Shanmugasundram reviewed gene: CYCS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v8.19 COX6A2 Achchuthan Shanmugasundram Classified gene: COX6A2 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.19 COX6A2 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be added with green rating to this panel as this gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX6A2/).
Likely inborn error of metabolism v8.19 COX6A2 Achchuthan Shanmugasundram Gene: cox6a2 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.18 COX6A2 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: COX6A2.
Likely inborn error of metabolism v8.18 COX6A2 Achchuthan Shanmugasundram reviewed gene: COX6A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.18 COX6A2 Achchuthan Shanmugasundram Deleted their review
Likely inborn error of metabolism v8.18 COX6A2 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.15
Likely inborn error of metabolism v8.18 COX6A2 Achchuthan Shanmugasundram gene: COX6A2 was added
gene: COX6A2 was added to Likely inborn error of metabolism. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: COX6A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX6A2 were set to 23460811; 31155743; 32744742
Phenotypes for gene: COX6A2 were set to Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062
Likely inborn error of metabolism v8.17 C2orf69 Achchuthan Shanmugasundram edited their review of gene: C2orf69: Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.17 COX11 Achchuthan Shanmugasundram edited their review of gene: COX11: Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.17 COX11 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene should be added with green rating to this panel as this gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/C2orf69/).; to: Comment on list classification: This gene should be added with green rating to this panel as this gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX11/).
Likely inborn error of metabolism v8.17 COX11 Achchuthan Shanmugasundram Classified gene: COX11 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.17 COX11 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be added with green rating to this panel as this gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/C2orf69/).
Likely inborn error of metabolism v8.17 COX11 Achchuthan Shanmugasundram Gene: cox11 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.16 COX11 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: COX11.
Likely inborn error of metabolism v8.16 COX11 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.15
Likely inborn error of metabolism v8.16 COX11 Achchuthan Shanmugasundram gene: COX11 was added
gene: COX11 was added to Likely inborn error of metabolism. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551; 38068960
Phenotypes for gene: COX11 were set to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Likely inborn error of metabolism v8.15 C2orf69 Achchuthan Shanmugasundram Classified gene: C2orf69 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.15 C2orf69 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be added with green rating to this panel as this gene has already been promoted to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/C2orf69/).
Likely inborn error of metabolism v8.15 C2orf69 Achchuthan Shanmugasundram Gene: c2orf69 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.14 C2orf69 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: C2orf69.
Likely inborn error of metabolism v8.14 C2orf69 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.15
Likely inborn error of metabolism v8.14 C2orf69 Achchuthan Shanmugasundram gene: C2orf69 was added
gene: C2orf69 was added to Likely inborn error of metabolism. Sources: Literature,NHS GMS,Expert Review Green
gene-checked tags were added to gene: C2orf69.
Mode of inheritance for gene: C2orf69 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C2orf69 were set to 34038740; 33945503
Phenotypes for gene: C2orf69 were set to Combined oxidative phosphorylation deficiency 53, OMIM:619423
Likely inborn error of metabolism v8.13 TOMM7 Achchuthan Shanmugasundram Classified gene: TOMM7 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.13 TOMM7 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported with biallelic variants in TOMM7 gene and with Garg-Mishra progeroid syndrome (MIM #620601).

This gene has already been recommended for promotion to green rating on R63 Possible mitochondrial disorder - nuclear genes (https://panelapp.genomicsengland.co.uk/panels/539/gene/TOMM7/) and Mitochondrial disorders (https://panelapp.genomicsengland.co.uk/panels/112/gene/TOMM7/) panels. Hence, this gene should also be recommended for promotion to green rating on this panel.
Likely inborn error of metabolism v8.13 TOMM7 Achchuthan Shanmugasundram Gene: tomm7 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.12 TOMM7 Achchuthan Shanmugasundram reviewed gene: TOMM7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v9.15 TOMM7 Achchuthan Shanmugasundram edited their review of gene: TOMM7: Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.12 TOMM7 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: TOMM7.
Tag Q3_24_NHS_review was removed from gene: TOMM7.
Tag Q2_25_ promote_green tag was added to gene: TOMM7.
Likely inborn error of metabolism v8.12 TOMM7 Achchuthan Shanmugasundram Entity copied from Possible mitochondrial disorder - nuclear genes v4.6
Likely inborn error of metabolism v8.12 TOMM7 Achchuthan Shanmugasundram gene: TOMM7 was added
gene: TOMM7 was added to Likely inborn error of metabolism. Sources: Literature,Expert Review Amber
Q3_24_promote_green, Q3_24_NHS_review tags were added to gene: TOMM7.
Mode of inheritance for gene: TOMM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOMM7 were set to 36282599; 36299998; 39333057
Phenotypes for gene: TOMM7 were set to Garg-Mishra progeroid syndrome, OMIM:620601; Garg-Mishra progeroid syndrome, MONDO:0957953
Likely inborn error of metabolism v8.11 SQOR Achchuthan Shanmugasundram Classified gene: SQOR as Amber List (moderate evidence)
Likely inborn error of metabolism v8.11 SQOR Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene is currently being recommended for green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/SQOR/), as there are two unrelated families and some functional evidence available in support of the association of SQOR gene with Sulfide:quinone oxidoreductase deficiency. Hence, this gene should also be promoted to green rating on this panel.
Likely inborn error of metabolism v8.11 SQOR Achchuthan Shanmugasundram Gene: sqor has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.10 SQOR Achchuthan Shanmugasundram Phenotypes for gene: SQOR were changed from Leigh syndrome to Sulfide:quinone oxidoreductase deficiency, OMIM:619221
Mitochondrial disorders v9.15 SQOR Achchuthan Shanmugasundram Phenotypes for gene: SQOR were changed from Leigh syndrome to Sulfide:quinone oxidoreductase deficiency, OMIM:619221
Likely inborn error of metabolism v8.9 SQOR Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.14
Likely inborn error of metabolism v8.9 SQOR Achchuthan Shanmugasundram gene: SQOR was added
gene: SQOR was added to Likely inborn error of metabolism. Sources: Literature,Expert Review Amber
Q2_25_ promote_green tags were added to gene: SQOR.
Mode of inheritance for gene: SQOR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SQOR were set to 32160317
Phenotypes for gene: SQOR were set to Leigh syndrome
Likely inborn error of metabolism v8.8 COX4I1 Achchuthan Shanmugasundram Phenotypes for gene: COX4I1 were changed from Mitochondrial Diseases; No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060
Likely inborn error of metabolism v8.7 COX4I1 Achchuthan Shanmugasundram Publications for gene: COX4I1 were set to
Likely inborn error of metabolism v8.7 COX4I1 Achchuthan Shanmugasundram Mode of inheritance for gene: COX4I1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.6 COX4I1 Achchuthan Shanmugasundram Classified gene: COX4I1 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.6 COX4I1 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should also be rated green on this panel as this has already been rated green on R356 Mitochondrial disorder with complex IV deficiency panel (https://panelapp.genomicsengland.co.uk/panels/537/gene/COX4I1/) and is being currently recommended for promotion to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX4I1/).

There are two unrelated cases and functional evidence in support of the association of this gene with Mitochondrial complex IV deficiency.
Likely inborn error of metabolism v8.6 COX4I1 Achchuthan Shanmugasundram Gene: cox4i1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.5 COX4I1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: COX4I1.
Likely inborn error of metabolism v8.5 COX4I1 Achchuthan Shanmugasundram changed review comment from: This gene should also be rated green on this panel as this has already been rated green on R356 Mitochondrial disorder with complex IV deficiency panel (https://panelapp.genomicsengland.co.uk/panels/537/gene/COX4I1/) and is being currently recommended for promotion to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX4I1/).

PMID:28766551 reported a 5-year-old girl identified with homozygous COX4I1 variant (p.(Lys101_Thr102delinsAsnSer)) and mitochondrial complex IV deficiency, which segregated with the disorder in the family.

PMID:31290619 reported two brothers of Iraqi descent, identified with a homozygous missense variant in the COX4I1 gene (p.(Pro152Thr)) and mitochondrial complex IV deficiency, which also segregated with the disorder in the family.

There is also functional evidence available from the above publications.

This gene is also associated with relevant phenotypes in OMIM (MIM #619060).; to: PMID:28766551 reported a 5-year-old girl identified with homozygous COX4I1 variant (p.(Lys101_Thr102delinsAsnSer)) and mitochondrial complex IV deficiency, which segregated with the disorder in the family.

PMID:31290619 reported two brothers of Iraqi descent, identified with a homozygous missense variant in the COX4I1 gene (p.(Pro152Thr)) and mitochondrial complex IV deficiency, which also segregated with the disorder in the family.

There is also functional evidence available from the above publications.

This gene is also associated with relevant phenotypes in OMIM (MIM #619060).
Likely inborn error of metabolism v8.5 COX4I1 Achchuthan Shanmugasundram reviewed gene: COX4I1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28766551, 31290619, 33578848; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v9.14 TOMM7 Achchuthan Shanmugasundram Classified gene: TOMM7 as Amber List (moderate evidence)
Mitochondrial disorders v9.14 TOMM7 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are three unrelated cases reported with biallelic TOMM7 variants and this gene has already been recommended for green rating on R63 Possible mitochondrial disorder - nuclear genes (https://panelapp.genomicsengland.co.uk/panels/539/gene/TOMM7/) panel, this gene is being recommended for promotion to green rating on this panel too.
Mitochondrial disorders v9.14 TOMM7 Achchuthan Shanmugasundram Gene: tomm7 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.13 TOMM7 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: TOMM7.
Tag Q3_24_NHS_review was removed from gene: TOMM7.
Tag Q2_25_ promote_green tag was added to gene: TOMM7.
Mitochondrial disorders v9.13 TOMM7 Achchuthan Shanmugasundram Entity copied from Possible mitochondrial disorder - nuclear genes v4.6
Mitochondrial disorders v9.13 TOMM7 Achchuthan Shanmugasundram gene: TOMM7 was added
gene: TOMM7 was added to Mitochondrial disorders. Sources: Literature,Expert Review Amber
Q3_24_promote_green, Q3_24_NHS_review tags were added to gene: TOMM7.
Mode of inheritance for gene: TOMM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOMM7 were set to 36282599; 36299998; 39333057
Phenotypes for gene: TOMM7 were set to Garg-Mishra progeroid syndrome, OMIM:620601; Garg-Mishra progeroid syndrome, MONDO:0957953
Mitochondrial disorders v9.12 HSPA9 Achchuthan Shanmugasundram Classified gene: HSPA9 as Amber List (moderate evidence)
Mitochondrial disorders v9.12 HSPA9 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has already been promoted to green rating on R63 Possible mitochondrial disorder - nuclear genes panel (https://panelapp.genomicsengland.co.uk/panels/539/gene/HSPA9/), in agreement with the NHS Genomic Medicine Service. Hence, this gene should be promoted to green rating on this panel in the next GMS update.
Mitochondrial disorders v9.12 HSPA9 Achchuthan Shanmugasundram Gene: hspa9 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.11 HSPA9 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: HSPA9.
Mitochondrial disorders v9.11 HSPA9 Achchuthan Shanmugasundram Phenotypes for gene: HSPA9 were changed from EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia; Epiphyseal, Vertebral, Ear, Nose, plus associated findings to Even-plus syndrome, OMIM:616854; Anemia, sideroblastic, 4, OMIM:182170
Mitochondrial disorders v9.10 HSPA9 Achchuthan Shanmugasundram Publications for gene: HSPA9 were set to PMID: 26598328
Mitochondrial disorders v9.9 HSPA9 Achchuthan Shanmugasundram edited their review of gene: HSPA9: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v9.9 HSPA9 Achchuthan Shanmugasundram reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 26491070, 26598328, 32869452, 35779070, 36052765; Phenotypes: Even-plus syndrome, OMIM:616854, Anemia, sideroblastic, 4, OMIM:182170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Possible mitochondrial disorder - nuclear genes v4.6 COX14 Achchuthan Shanmugasundram Phenotypes for gene: COX14 were changed from ?Mitochondrial complex IV deficiency, 220110 to ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053
Possible mitochondrial disorder - nuclear genes v4.5 COX14 Achchuthan Shanmugasundram Publications for gene: COX14 were set to
Possible mitochondrial disorder - nuclear genes v4.4 COX14 Achchuthan Shanmugasundram Classified gene: COX14 as Green List (high evidence)
Possible mitochondrial disorder - nuclear genes v4.4 COX14 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has also been demoted from green to amber on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX14/) in response to review from Zornitza Stark (Australian Genomics), and in agreement with the NHS Genomic Medicine Service. Hence, this gene is recommended for demotion on this panel and opinion is being sought from the NHS mitochondrial specialist teams on this.
Possible mitochondrial disorder - nuclear genes v4.4 COX14 Achchuthan Shanmugasundram Gene: cox14 has been classified as Green List (High Evidence).
Possible mitochondrial disorder - nuclear genes v4.3 COX14 Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: COX14.
Tag Q2_25_ demote_amber tag was added to gene: COX14.
Mitochondrial disorder with complex IV deficiency v4.5 COX14 Achchuthan Shanmugasundram changed review comment from: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence.

This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.; to: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence.

This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.
Possible mitochondrial disorder - nuclear genes v4.3 COX14 Achchuthan Shanmugasundram changed review comment from: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence.

This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.; to: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence.

This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.
Mitochondrial disorder with complex IV deficiency v4.5 COX14 Achchuthan Shanmugasundram changed review comment from: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence.

This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.; to: PMID:22243966 reported one family with a homozygous missense COX14 (C12orf62) variant presenting with severe congenital lactic acidosis and dysmorphic features. There is also functional evidence available in support of the association. However, there is no additional evidence associating this gene to disease in humans. Hence, this gene should be rated amber with the available evidence.

This gene is rated amber on the Mitochondrial disease panel in PanelApp Australia (https://panelapp-aus.org/panels/203/gene/COX14/). It is tentatively associated with a disease phenotype in OMIM (MIM #619053) and has limited rating on the DD panel in Gene2Phenotype database.
Possible mitochondrial disorder - nuclear genes v4.3 COX14 Achchuthan Shanmugasundram reviewed gene: COX14: Rating: AMBER; Mode of pathogenicity: None; Publications: 22243966; Phenotypes: ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v4.5 COX14 Achchuthan Shanmugasundram Classified gene: COX14 as Green List (high evidence)
Mitochondrial disorder with complex IV deficiency v4.5 COX14 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has also been demoted from green to amber on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX14/) in response to review from Zornitza Stark (Australian Genomics), and in agreement with the NHS Genomic Medicine Service. Hence, this gene is recommended for demotion on this panel and opinion is being sought from the NHS mitochondrial specialist teams on this.
Mitochondrial disorder with complex IV deficiency v4.5 COX14 Achchuthan Shanmugasundram Gene: cox14 has been classified as Green List (High Evidence).
Possible mitochondrial disorder - nuclear genes v4.3 BTD Achchuthan Shanmugasundram changed review comment from: Zornitza Stark (Australian Genomics) has rated BTD red on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/BTD/) and has requested that the association between BTD variants and mitochondrial disease could be reviewed.

This gene has been demoted to amber in Mitochondrial disorders panel after being reviewed and agreed by the NHS Genomic Medicine Service. Hence, this gene is now recommended for demotion to amber on this panel and opinion is being sought from NHS mitochondrial specialist teams on this.; to: Zornitza Stark (Australian Genomics) has rated BTD red on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/BTD/) and has requested that the association between BTD variants and mitochondrial disease could be reviewed.

This gene has been demoted to amber in Mitochondrial disorders panel after being reviewed and agreed by the NHS Genomic Medicine Service. Hence, this gene is now recommended for demotion to amber on this panel and opinion is being sought from the NHS mitochondrial specialist teams on this.
Possible mitochondrial disorder - nuclear genes v4.3 ANO10 Achchuthan Shanmugasundram changed review comment from: Zornitza Stark (Australian Genomics) has rated ANO10 red on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/ANO10/) and has requested that the association between ANO10 variants and mitochondrial disease could be reviewed. She suggested that the reported CoQ10 deficiency appears to be secondary in the cited publication.

This gene has been demoted to amber in Mitochondrial disorders panel after reviewed and agreed by the NHS Genomic Medicine Service. Hence, this gene is now being recommended for demotion to amber on this panel and opinion is being sought from NHS mitochondrial specialist teams on this.; to: Zornitza Stark (Australian Genomics) has rated ANO10 red on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/ANO10/) and has requested that the association between ANO10 variants and mitochondrial disease could be reviewed. She suggested that the reported CoQ10 deficiency appears to be secondary in the cited publication.

This gene has been demoted to amber in Mitochondrial disorders panel after being reviewed and agreed by the NHS Genomic Medicine Service. Hence, this gene is now recommended for demotion to amber on this panel and opinion is being sought from the NHS mitochondrial specialist teams on this.
Possible mitochondrial disorder - nuclear genes v4.3 BTD Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: BTD.
Tag Q2_25_ demote_amber tag was added to gene: BTD.
Possible mitochondrial disorder - nuclear genes v4.3 BTD Achchuthan Shanmugasundram reviewed gene: BTD: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v4.3 ANO10 Achchuthan Shanmugasundram Phenotypes for gene: ANO10 were changed from Spinocerebellar ataxia, autosomal recessive 10, 613728 to Spinocerebellar ataxia, autosomal recessive 10, OMIM:613728
Possible mitochondrial disorder - nuclear genes v4.2 ANO10 Achchuthan Shanmugasundram Publications for gene: ANO10 were set to
Possible mitochondrial disorder - nuclear genes v4.1 ANO10 Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: ANO10.
Tag Q2_25_ demote_amber tag was added to gene: ANO10.
Possible mitochondrial disorder - nuclear genes v4.1 ANO10 Achchuthan Shanmugasundram reviewed gene: ANO10: Rating: AMBER; Mode of pathogenicity: None; Publications: 25778941; Phenotypes: Spinocerebellar ataxia, autosomal recessive 10, OMIM:613728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v3.1 MYLK3 Matthew Edwards reviewed gene: MYLK3: Rating: AMBER; Mode of pathogenicity: None; Publications: 17885681, 31244672, 37128901, 32213617, 29235529, 30690923; Phenotypes: Dilated Cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v9.9 SQOR Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SQOR.
Mitochondrial disorders v9.9 SQOR Achchuthan Shanmugasundram reviewed gene: SQOR: Rating: GREEN; Mode of pathogenicity: None; Publications: 32160317; Phenotypes: Sulfide:quinone oxidoreductase deficiency, OMIM:619221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v4.4 SQOR Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619221).
Mitochondrial disorder with complex IV deficiency v4.4 SQOR Achchuthan Shanmugasundram Phenotypes for gene: SQOR were changed from Leigh syndrome to Sulfide:quinone oxidoreductase deficiency, OMIM:619221
Mitochondrial disorders v9.9 SQOR Achchuthan Shanmugasundram Classified gene: SQOR as Amber List (moderate evidence)
Mitochondrial disorders v9.9 SQOR Achchuthan Shanmugasundram Gene: sqor has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.8 SQOR Achchuthan Shanmugasundram Entity copied from Mitochondrial disorder with complex IV deficiency v4.3
Mitochondrial disorders v9.8 SQOR Achchuthan Shanmugasundram gene: SQOR was added
gene: SQOR was added to Mitochondrial disorders. Sources: Literature,Expert Review Green
Mode of inheritance for gene: SQOR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SQOR were set to 32160317
Phenotypes for gene: SQOR were set to Leigh syndrome
Mitochondrial disorders v9.7 COX14 Achchuthan Shanmugasundram Phenotypes for gene: COX14 were changed from Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110 to ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053
Mitochondrial disorders v9.6 COX14 Achchuthan Shanmugasundram edited their review of gene: COX14: Changed phenotypes to: ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053
Mitochondrial disorders v9.6 COX4I1 Achchuthan Shanmugasundram Phenotypes for gene: COX4I1 were changed from Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060 to Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060
Mitochondrial disorders v9.5 COX4I1 Achchuthan Shanmugasundram Phenotypes for gene: COX4I1 were changed from No OMIM phenotype; Mitochondrial Diseases to Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060
Mitochondrial disorders v9.5 COX4I1 Achchuthan Shanmugasundram Publications for gene: COX4I1 were set to
Mitochondrial disorders v9.4 COX4I1 Achchuthan Shanmugasundram Classified gene: COX4I1 as Amber List (moderate evidence)
Mitochondrial disorders v9.4 COX4I1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are two unrelated cases and functional evidence available in support of the association, this gene can be promoted to green rating in the next GMS update.
Mitochondrial disorders v9.4 COX4I1 Achchuthan Shanmugasundram Gene: cox4i1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.3 COX4I1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: COX4I1.
Mitochondrial disorders v9.3 COX4I1 Achchuthan Shanmugasundram reviewed gene: COX4I1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28766551, 31290619, 33578848; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 16, OMIM:619060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v4.3 COX14 Achchuthan Shanmugasundram Publications for gene: COX14 were set to
Mitochondrial disorder with complex IV deficiency v4.2 COX14 Achchuthan Shanmugasundram Phenotypes for gene: COX14 were changed from ?Mitochondrial complex IV deficiency, 220110 to ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053
Mitochondrial disorder with complex IV deficiency v4.1 COX14 Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: COX14.
Tag Q2_25_ demote_amber tag was added to gene: COX14.
Mitochondrial disorder with complex IV deficiency v4.1 COX14 Achchuthan Shanmugasundram reviewed gene: COX14: Rating: AMBER; Mode of pathogenicity: None; Publications: 22243966; Phenotypes: ?Mitochondrial complex IV deficiency, nuclear type 10, OMIM:619053; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.1 RFC1 Lauren Turton Deleted their review
Hereditary ataxia with onset in adulthood v8.5 RFC1 Lauren Turton Deleted their review
Hereditary ataxia with onset in adulthood v8.5 RFC1 Lauren Turton Deleted their comment
Hereditary neuropathy or pain disorder v7.1 RFC1 Lauren Turton reviewed gene: RFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36289003, 36478048, 35883251, 36250766, 36524104; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (OMIM: 614575); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v8.5 RFC1 Lauren Turton changed review comment from: In total 14 patients from 11 unrelated families who have clinically defined CANVAS and are compound heterozygous for a null allele with the (AAGGG)n expansion.
Ronco et al., 2023 PMID: 36289003
7 patients from 5 unrelated families with clinically defined CANVAS with a heterozygous (AAGGG)n expansion in trans with a truncating RFC1 variant. Family 1 and family 4 has two affected siblings.
Weber et al., 2023 PMID: 36478048
2 patients compound heterozygous for null variants with the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
Benkirane et al. 2022 PMID: 35883251
2 patients compound heterozygous for null variants and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
Arteche-López et al., 2023 PMID:36250766
2 affected sisters with a nonsense variant and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
King et al., 2022 PMID: 36524104
1 patient with a nonsense variant confirmed in trans with the (AAGGG)n expansion, phenotype characteristic of CANVAS.

Suggest that patients who have been tested for CANVAS, upon analysis of the WGS results if they are known to be heterozygous for (AAGGG)n then analysts should manually check for any LoF RFC1 variants.; to: In total 14 patients from 11 unrelated families who have clinically defined CANVAS and are compound heterozygous for a null allele with the (AAGGG)n expansion.
Ronco et al., 2023 PMID: 36289003
7 patients from 5 unrelated families with clinically defined CANVAS with a heterozygous (AAGGG)n expansion in trans with a truncating RFC1 variant. Family 1 and family 4 has two affected siblings.
Weber et al., 2023 PMID: 36478048
2 patients compound heterozygous for null variants with the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
Benkirane et al. 2022 PMID: 35883251
2 patients compound heterozygous for null variants and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
Arteche-López et al., 2023 PMID:36250766
2 affected sisters with a nonsense variant and the (AAGGG)n expansion, their phenotypes were characteristic of CANVAS.
King et al., 2022 PMID: 36524104
1 patient with a nonsense variant confirmed in trans with the (AAGGG)n expansion, phenotype characteristic of CANVAS.

Suggest that patients who have been tested for CANVAS, upon analysis of the WGS results if they are known to be heterozygous for (AAGGG)n then analysts should manually check for any LoF RFC1 variants.
Hereditary ataxia with onset in adulthood v8.5 RFC1 Lauren Turton reviewed gene: RFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36289003, 36478048, 35883251, 36250766, 36524104; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (OMIM: 614575); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory disorders v2.5 TBK1 Dorota Rowczenio gene: TBK1 was added
gene: TBK1 was added to Autoinflammatory disorders. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: TBK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBK1 were set to PMID: 34363755; PMID: 34210994; PMID: 28148298; PMID: 34363755
Phenotypes for gene: TBK1 were set to chronic and systemic autoinflammation driven by TNF-induced cell death
Review for gene: TBK1 was set to GREEN
Added comment: Sources: Expert list, Expert Review, Literature
Bardet Biedl syndrome v2.7 IFT57 Achchuthan Shanmugasundram Classified gene: IFT57 as Amber List (moderate evidence)
Bardet Biedl syndrome v2.7 IFT57 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is one patient and functional evidence reported, IFT57 should be rated amber with the current evidence.
Bardet Biedl syndrome v2.7 IFT57 Achchuthan Shanmugasundram Gene: ift57 has been classified as Amber List (Moderate Evidence).
Bardet Biedl syndrome v2.6 IFT57 Achchuthan Shanmugasundram Phenotypes for gene: IFT57 were changed from Bardet-Biedl syndrome to Bardet-Biedl syndrome, MONDO:0015229
Bardet Biedl syndrome v2.5 IFT57 Achchuthan Shanmugasundram Publications for gene: IFT57 were set to PMID: 40273360
Bardet Biedl syndrome v2.4 IFT57 Achchuthan Shanmugasundram reviewed gene: IFT57: Rating: AMBER; Mode of pathogenicity: None; Publications: 40273360; Phenotypes: Bardet-Biedl syndrome, MONDO:0015229; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory disorders v2.5 TMEM173 Dorota Rowczenio commented on gene: TMEM173
Autoinflammatory disorders v2.5 RIPK1 Dorota Rowczenio gene: RIPK1 was added
gene: RIPK1 was added to Autoinflammatory disorders. Sources: Expert list,Expert Review,Literature,Research
Mode of inheritance for gene: RIPK1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: RIPK1 were set to PMID: 31911632; PMID: 31827281; PMID:31827280; PMID: 39557292; PMID: 37452601; PMID:35716229; PMID:35786329
Phenotypes for gene: RIPK1 were set to Autoinflammation with episodic fever and lymphadenopathy (autosomal dominant); Immunodeficiency 57 with autoinflammation (autosomal recessive)
Review for gene: RIPK1 was set to GREEN
Added comment: Sources: Expert list, Expert Review, Literature, Research
Autoinflammatory disorders v2.5 ALPK1 Dorota Rowczenio changed review comment from: Sources: Expert list; to: Sources: Expert list
Autoinflammatory disorders v2.5 RELA Dorota Rowczenio gene: RELA was added
gene: RELA was added to Autoinflammatory disorders. Sources: Expert list,Expert Review,Literature,Research
Mode of inheritance for gene: RELA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RELA were set to PMID: 36926348; PMID: 32969189; PMID: 35412596; PMID: 28600438
Phenotypes for gene: RELA were set to Autoinflammatory disease, familial, behcet-like 3
Review for gene: RELA was set to GREEN
Added comment: Sources: Expert list, Expert Review, Literature, Research
Autoinflammatory disorders v2.5 POMP Dorota Rowczenio gene: POMP was added
gene: POMP was added to Autoinflammatory disorders. Sources: Expert Review,Literature,Research,ClinGen
Mode of inheritance for gene: POMP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POMP were set to PMID: 38111302; PMID: 29805043
Phenotypes for gene: POMP were set to Proteasome-associated autoinflammatory syndrome 2
Review for gene: POMP was set to GREEN
Added comment: Sources: Expert Review, Literature, Research, ClinGen
Autoinflammatory disorders v2.5 IKBKG Dorota Rowczenio reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35120036, PMID: 35289316, PMID: 20133626, PMID: 21722947, PMID: 35163099, PMID: 39264518; Phenotypes: Autoinflammatory disease, systemic, X-linked; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Autoinflammatory disorders v2.5 ELF4 Dorota Rowczenio gene: ELF4 was added
gene: ELF4 was added to Autoinflammatory disorders. Sources: Expert list,Literature
Mode of inheritance for gene: ELF4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ELF4 were set to PMID: 35266071; PMID: 34326534; PMID: 39976696; PMID: 39563044; PMID: 38773005; PMID: 38231408; PMID: 36823308
Phenotypes for gene: ELF4 were set to Autoinflammatory syndrome, familial, X-linked, Behcet-like 2
Review for gene: ELF4 was set to GREEN
Added comment: Sources: Expert list, Literature
Autoinflammatory disorders v2.5 COPA Dorota Rowczenio reviewed gene: COPA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27048656, PMID: 31455335, PMID: 3976718, PMID: 34900872, PMID: 30385646, Jensson, B.O., Hansdottir, S., Arnadottir, G.A. et al. COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA . BMC Med Genet 18, 129 (2017).; Phenotypes: Autoimmune interstitial lung, joint, and kidney disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v2.5 ALPK1 Dorota Rowczenio gene: ALPK1 was added
gene: ALPK1 was added to Autoinflammatory disorders. Sources: Expert list
Mode of inheritance for gene: ALPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALPK1 were set to PMID: 30967659; PMID: 36332842; PMID: 38251500; PMID: 40069099; PMID: 35868845
Phenotypes for gene: ALPK1 were set to Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis, and migraine Headache syndrome (ROSAH)
Penetrance for gene: ALPK1 were set to unknown
Review for gene: ALPK1 was set to GREEN
Added comment: Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v7.2 NOTCH3 Lauren Turton reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39191170; Phenotypes: Spasticity, stroke, periatrial white matter volume loss; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v8.1 NOTCH3 Lauren Turton gene: NOTCH3 was added
gene: NOTCH3 was added to Childhood onset hereditary spastic paraplegia. Sources: NHS GMS
Mode of inheritance for gene: NOTCH3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOTCH3 were set to 39191170
Phenotypes for gene: NOTCH3 were set to Spasticity, stroke, periatrial white matter volume loss
Review for gene: NOTCH3 was set to GREEN
Added comment: Twenty-five patients from 17 unrelated families harbouring homozygous or compound heterozygous variants in NOTCH3. Among them 18 carried LoF variants.
Patients had a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Mean age at the onset of symptoms was 28 months, ranging from congenital to 17 years old.
Showed that patients with the biallelic LoF variants had a different phenotype to that seen in CADASIL.
Sources: NHS GMS
Renal tubulopathies v5.1 OCRL Beccy Cummings reviewed gene: OCRL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Renal tubulopathies v5.1 CLCN5 Beccy Cummings reviewed gene: CLCN5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Respiratory ciliopathies including non-CF bronchiectasis v4.1 WFDC2 Steven Cowman edited their review of gene: WFDC2: Added comment: In addition to the 11 individuals reported in PMID 38626355 (see earlier review) there is now a further report (PMID 40401042) of three unrelated individuals from Japan with bronchiectasis who were all found to be homozygous for the same missense variant of WFDC2 (p.Cys97Trp).

In keeping with the first series, all patients were reported to have upper lobe predominant bronchiectasis, sinus disease and low nasal NO, although ciliary ultrastructure was normal on EM and no pathogenic variants in CFTR or PCD-causing genes were found.; Changed publications to: PMID: 38626355, 40401042
Respiratory ciliopathies including non-CF bronchiectasis v4.1 WFDC2 Steven Cowman changed review comment from: Reported in 11 individuals from 10 different families, all of whom had nasal polyposis and nine with diffuse bronchiectasis, aged between 7 and 52 years. All those tested had impaired lung function (8/11) and Pseudomonas isolation (8/11). The bronchiectasis was noted to have an upper-lobe predominance in a manner similar to CF.

Low nasal NO levels were reported in all (9/11) tested individuals, although no disease causing variants were found in CFTR or PCD-related genes and mucociliary studies found clearance within the normal range, and EM in 8 individuals found normal ciliary ultrastructure. Sweat chloride was normal in all (9/11) tested individuals.

Seven pathogenic WFDC2 variants were found, with one missense variant (c.145T>C; p.Cys49Arg) found in 12/22 alleles from 8/11 individuals. Expression analysis of healthy controls found WFDC2 to be expressed in the respiratory epithelium. Glycosylated WFDC2 protein was detectable in the saliva of a healthy control and one heterozygous mother of an affected individual, but not three tested affected individuals. Structural analysis suggested the c.145T>C mutation disrupts N-linked glycosylation of WFDC2 and hence impairs secretion.
Sources: Literature; to: Reported in 11 individuals from 10 different families, all of whom had nasal polyposis and nine with diffuse bronchiectasis, aged between 7 and 52 years. All those tested had impaired lung function (8/11) and Pseudomonas isolation (8/11). The bronchiectasis was noted to have an upper-lobe predominance in a manner similar to CF.

Low nasal NO levels were reported in all (9/11) tested individuals, although no disease causing variants were found in CFTR or PCD-related genes and mucociliary studies found clearance within the normal range, and EM in 8 individuals found normal ciliary ultrastructure. Sweat chloride was normal in all (9/11) tested individuals.

Seven pathogenic WFDC2 variants were found, with one missense variant (c.145T>C; p.Cys49Arg) found in 12/22 alleles from 8/11 individuals. Expression analysis of healthy controls found WFDC2 to be expressed in the respiratory epithelium. Glycosylated WFDC2 protein was detectable in the saliva of a healthy control and one heterozygous mother of an affected individual, but not three tested affected individuals. Structural analysis suggested the c.145T>C mutation disrupts N-linked glycosylation of WFDC2 and hence impairs secretion.
Sources: Literature
Paediatric disorders - additional genes v7.1 MC4R Ian Berry gene: MC4R was added
gene: MC4R was added to Paediatric disorders - additional genes. Sources: Expert Review
Mode of inheritance for gene: MC4R was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Penetrance for gene: MC4R were set to Incomplete
Review for gene: MC4R was set to GREEN
Added comment: Well-established OMIM association. Gene on R149 Severe Early Onset Obesity panel (green). Many R27 referrals include ID & obesity/overgrowth so may be a partial explanation for many patients referred. This is the primary/most common R149 gene that it not currently on the R27 panel and inclusion would minimise management of re-analysis requests for R149 for patient who meet both the R27 and potentially R149 eligibility criteria.
Sources: Expert Review
Familial tumours of the nervous system v2.1 CDKN2A Terri McVeigh gene: CDKN2A was added
gene: CDKN2A was added to Familial tumours of the nervous system. Sources: Expert Review,Literature
Mode of inheritance for gene: CDKN2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDKN2A were set to PMID 24884915; 8317504; 9622062; 10797439; 17440112; 26794401; 29263814; 28699883; 28754699; 35422439; 38936911
Phenotypes for gene: CDKN2A were set to MELANOMA; PANCREATIC CANCER; ASTROCYTOMA; GLIOBLASTOMA; SCHWANNOMA; NEUROFIBROMA; MENINGIOMA; MALIGNANT PERIPHERAL NERVE SHEATH TUMOURS
Penetrance for gene: CDKN2A were set to Incomplete
Review for gene: CDKN2A was set to GREEN
Added comment: Phenotype including neural tumours discussed at Joint Dutch/UKCGG Cancer Case Meeting 2025
Sources: Expert Review, Literature
Inherited polyposis and early onset colorectal cancer - germline testing v3.1 MBD4 Terri McVeigh reviewed gene: MBD4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35460607, 30049810, 35381620, 32421892, 32239153; Phenotypes: MBD4-Associated Neoplasia Syndrome: Colonic polyposis, colon cancer, uveal melanoma, acute myeloid leukaemia, schwannoma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited breast cancer and ovarian cancer v2.11 BARD1 Terri McVeigh gene: BARD1 was added
gene: BARD1 was added to Inherited breast cancer and ovarian cancer. Sources: NHS GMS,Expert Review,Literature
Mode of inheritance for gene: BARD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BARD1 were set to PMID: 33471991
Phenotypes for gene: BARD1 were set to breast cancer
Penetrance for gene: BARD1 were set to Incomplete
Review for gene: BARD1 was set to GREEN
Added comment: Discussed at Cancer/Scientific Leads/UKCGG council meeting re Test Directory updates 2025/2026 (30/01/2025) - consensus was that evidence is sufficient to warrant addition of this gene to R208 panel. Strong evidence indicating that BARD1 is a moderate-risk breast cancer susceptibility gene, with risks associated with pathogenic variants in this gene similar to those associated with variants in other moderate risk genes already included on the panel (PMID: 33471991).

We propose reporting should be restricted to truncating variants, and will provide gene-specific reporting guidance to GLHs via UKCGG/CanVIG as we have for other moderate risk genes (https://www.ukcgg.org/information-education/exceptional-variantsgene-specific-variant-reporting/)
Sources: NHS GMS, Expert Review, Literature
Adult onset neurodegenerative disorder v8.1 ISCA-37446-Loss Lauren Turton Region: ISCA-37446-Loss was added
Region: ISCA-37446-Loss was added to Adult onset neurodegenerative disorder. Sources: NHS GMS
Mode of inheritance for Region: ISCA-37446-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for Region: ISCA-37446-Loss were set to 24018986; 27017469
Phenotypes for Region: ISCA-37446-Loss were set to DIGEORGE SYNDROME; DGS (OMIM: 188400)
Penetrance for Region: ISCA-37446-Loss were set to Complete
Review for Region: ISCA-37446-Loss was set to AMBER
Region: ISCA-37446-Loss was marked as current diagnostic
Added comment: PMID: 24018986 159 adults diagnosed with 22q11.2DS. Four of 68 subjects (5.9%) aged 35 to 64 years with 22q11.2 deletions had been diagnosed as having PD (standardized morbidity ratio = 91.7; 95% CI, 25.0–234.8). Prevalence 5.9% in this cohort, however many of the individuals in 18-34 age group (n=90).

PMID: 27017469 We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001).

In Sheffield we also have a case with DiGeorge syndrome, that was referred for genetic testing due to parkinsonism as the primary referral reason. The patient also had other clinical features compatible with DiGeorge syndrome.

Added as amber as it is likely these patients will have other features that make them eligible for alternative panels such as R29.
Sources: NHS GMS
Retinal disorders v8.4 VSX2 Beisi Xu reviewed gene: VSX2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 36264558, 24001013, 20414678; Phenotypes: NIGHT BLINDNESS, CONGENITAL STATIONARY, pan-bipolar cell dysfunction, LENS SUBLUXATION, Microphthalmia, isolated 2 610093, Microphthalmia/coloboma 3 610092, CATARACTS, IRIS ABNORMALITIES; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v8.1 ATXN10_ATTCT Sarah Leigh Tag Q2_25_expert_review tag was added to STR: ATXN10_ATTCT.
Ataxia and cerebellar anomalies - narrow panel v8.3 ATXN10_ATTCT Sarah Leigh Tag Q2_25_expert_review tag was added to STR: ATXN10_ATTCT.
Adult onset neurodegenerative disorder v8.1 CACNA1A_CAG Sarah Leigh Tag Q2_25_expert_review tag was added to STR: CACNA1A_CAG.
Ataxia and cerebellar anomalies - narrow panel v8.3 CACNA1A_CAG Sarah Leigh Tag Q2_25_expert_review tag was added to STR: CACNA1A_CAG.
Retinal disorders v8.4 DYRK1A Siying Lin gene: DYRK1A was added
gene: DYRK1A was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: DYRK1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DYRK1A were set to PMID: 40405340; 36736451
Phenotypes for gene: DYRK1A were set to FEVR
Mode of pathogenicity for gene: DYRK1A was set to Other
Review for gene: DYRK1A was set to GREEN
Added comment: PMID 36736451: one individual with DYRK1A syndrome and anomalous retinal vasculature.
PMID 40405340: two individuals with FEVR-like presentations and later likely disease-causing DKRY1A variants identified; the retinal phenotype can be the presenting feature of DYRK1A syndrome
Sources: Literature
Monogenic hearing loss v5.8 GJB6 Eleanor Williams changed review comment from: Since this gene was last reviewed in 2020 there are have been two reports of the same variant in the gene associated with hearing loss in unrelated families.

PMID: 40369851 - Elmakhzen et al 2025 - reports a 3rd case with of individuals carrying the same missense variant (ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) and syndromic hearing loss identified through WGS. The patient, a 13 year old girl, who presented with both congenital hearing loss and ectodermal anomalies. Both her grandfather and one maternal uncle showed congenital bilateral deafness (no genetic analysis). However the variant was found to be de novo in this proband with neither parent carrying the variant. The variant is absent from Gnomad 4.1.0.

Duzkale et al 2022 - https://mednexus.org/doi/full/10.1097/JD9.0000000000000231 (not in PubMed). report a Turkish girl with nonsyndromic Hearing loss with p. Gly59Arg heterozygous missense mutation in the GJB6 gene. The variant was identified through panel sequencing of 75 genes from the PanelApp hearing loss panel, including GJB6. The variant was also present heterozygously in the mother and grandfather, who both had hearing loss and palmoplantar hyperkeratosis. The p.Gly59Arg mutation of GJB6 was first described in 2009 in a 32-year-old Japanese woman with mild palmoplantar keratoderma, knuckle pads, and severe sensorineural HL (PMID: 19416251).; to: Since this gene was last reviewed in 2020 there are have been two reports of the same variant in the gene associated with hearing loss in unrelated families.

PMID: 40369851 - Elmakhzen et al 2025 - reports a 3rd case with of individuals carrying the same missense variant (ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) and bilateral syndromic hearing loss identified through WGS. The patient, a 13 year old girl, who presented with both congenital hearing loss and ectodermal anomalies. Both her grandfather and one maternal uncle showed congenital bilateral deafness (no genetic analysis). However the variant was found to be de novo in this proband with neither parent carrying the variant. The variant is absent from Gnomad 4.1.0.

Duzkale et al 2022 - https://mednexus.org/doi/full/10.1097/JD9.0000000000000231 (not in PubMed). report a Turkish girl with nonsyndromic bilateral hearing loss with p. Gly59Arg heterozygous missense mutation in the GJB6 gene. The variant was identified through panel sequencing of 75 genes from the PanelApp hearing loss panel, including GJB6. The variant was also present heterozygously in the mother and grandfather, who both had hearing loss and palmoplantar hyperkeratosis. The p.Gly59Arg mutation of GJB6 was first described in 2009 in a 32-year-old Japanese woman with mild palmoplantar keratoderma, knuckle pads, and severe sensorineural HL (PMID: 19416251).
Monogenic hearing loss v5.8 GJB6 Eleanor Williams commented on gene: GJB6: Since this gene was last reviewed in 2020 there are have been two reports of the same variant in the gene associated with hearing loss in unrelated families.

PMID: 40369851 - Elmakhzen et al 2025 - reports a 3rd case with of individuals carrying the same missense variant (ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) and syndromic hearing loss identified through WGS. The patient, a 13 year old girl, who presented with both congenital hearing loss and ectodermal anomalies. Both her grandfather and one maternal uncle showed congenital bilateral deafness (no genetic analysis). However the variant was found to be de novo in this proband with neither parent carrying the variant. The variant is absent from Gnomad 4.1.0.

Duzkale et al 2022 - https://mednexus.org/doi/full/10.1097/JD9.0000000000000231 (not in PubMed). report a Turkish girl with nonsyndromic Hearing loss with p. Gly59Arg heterozygous missense mutation in the GJB6 gene. The variant was identified through panel sequencing of 75 genes from the PanelApp hearing loss panel, including GJB6. The variant was also present heterozygously in the mother and grandfather, who both had hearing loss and palmoplantar hyperkeratosis. The p.Gly59Arg mutation of GJB6 was first described in 2009 in a 32-year-old Japanese woman with mild palmoplantar keratoderma, knuckle pads, and severe sensorineural HL (PMID: 19416251).
Monogenic hearing loss v5.8 GJB6 Eleanor Williams Phenotypes for gene: GJB6 were changed from Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977; Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977 to Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977
Malformations of cortical development v7.3 NFIA Nour Elkhateeb gene: NFIA was added
gene: NFIA was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: NFIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFIA were set to 36553517,
Added comment: cortical malformations reported in PMID 36553517, and other CNS malformations reported in PMID 36553517 and PMID: 27081522
Sources: Literature
Amelogenesis imperfecta v4.1 LAMC2 Claire Smith edited their review of gene: LAMC2: Added comment: PMID: 37228816 Bloch-Zupan et al. 2023 report one family with LAMC2 mutations as part of a larger panel of sequenced individuals. They report a single child as being affected with a hypoplastic/hypomature AI phenotype. The primary dentition is described as showing thin white opaque enamel.

They identified a heterozygous LAMC2 variant NM_005562.3: c.493C>T; p.(Arg165Cys) with an allele frequency of 0.2% in GnomAD, predicted deleterious by SIFT (v4.0.3) and PolyPhen-2 and located in the Laminin EGF domain. The authors highlight that the enamel formation defects in mice (Wazen et al., 2016) and the patient’s phenotype are similar to the one another. The allele is inherited from her mother but the mother's phenotype was not available.

Notably the patient was sequenced using whole exome sequencing using the following parameters: Non-pathogenic variants were filtered out via: 1) variants represented with an allele frequency of more than 1% in public variation databases including the 1,000 Genomes, the GnomAD database or their internal exome database, variants in 5′ or 3′ UTR, variants with intronic locations and no prediction of local splice effect, and synonymous variants without pathogenic prediction of local splice effect.

Annotations of structural variations (SV) were performed by AnnotSV (Geoffroy et al., 2018). No other findings are presented for the individual.

In conclusion, I do not believe this is strong enough evidence to conclude that this LAMC2 mutation is the cause of disease in this family due to the lack of phenotype information for the mother or any modelling of the effects of the variant, but it is suggestive and additional publications with further families might provide more solid evidence to elevate this gene to green. I would currently consider this gene to be rated amber.; Changed rating: AMBER; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.4 CFI Siying Lin gene: CFI was added
gene: CFI was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: CFI was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CFI were set to Early Onset Drsen Maculopathy
Penetrance for gene: CFI were set to unknown
Review for gene: CFI was set to AMBER
Added comment: A rare heterozygous variant in CFI was identified in two Tunisian families: one affected by early-onset drusen maculopathy and the other by “advanced AMD,” although the age of onset in the latter is unknown (PMID: 25986072). Functional studies provide evidence that rare, highly penetrant CFI variants contribute to the genetic burden of AMD (PMIDs: 25788521, 23685748), supporting a potential mechanistic link between these variants and dominantly inherited early-onset drusen maculopathy.
Sources: Literature
Monogenic hearing loss v5.7 GJB6 Sarah Leigh Tag cnv tag was added to gene: GJB6.
Tag Q2_25_ promote_green tag was added to gene: GJB6.
Tag Q2_25_expert_review tag was added to gene: GJB6.
Tag Q2_25_ NHS_review tag was added to gene: GJB6.
Monogenic hearing loss v5.7 GJB6 Sarah Leigh Phenotypes for gene: GJB6 were changed from hearing loss; Deafness, autosomal dominant 3B, 612643; Deafness, autosomal recessive 1B, 612645; Deafness, digenic GJB2/GJB6, 220290; Ectodermal dysplasia 2, Clouston type, 129500; Nonsyndromic Hearing Loss, Dominant to Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977; Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977
Monogenic hearing loss v5.6 GJB6 Sarah Leigh Publications for gene: GJB6 were set to 10471490; 11896458; 11807148; 15150777; 24522190; 29921236; 39498320; 19416251; 40369851
Monogenic hearing loss v5.5 GJB6 Sarah Leigh reviewed gene: GJB6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 1B, OMIM:612645, autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977, Deafness, autosomal recessive 1B, OMIM:612645, autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v5.5 GJB2 Sarah Leigh Tag cnv tag was added to gene: GJB2.
Monogenic hearing loss v5.5 GJB6 Sarah Leigh Publications for gene: GJB6 were set to 10471490; 24522190; 39498320; 19416251; 40369851
Monogenic hearing loss v5.4 GJB6 Sarah Leigh Publications for gene: GJB6 were set to PMID:10471490; 10570462; 10610709; 11017065; 11807148; 11874494; 11896458; 12419304; 12490528; 12668604; 14571368; 15150777; 15213106; 15638823; 15994881; 17041943; 18324688; 20858605; 8663509; 9139825; 9799458
Retinal disorders v8.4 CYP2U1 Cassandra Smith gene: CYP2U1 was added
gene: CYP2U1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: CYP2U1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP2U1 were set to PMID: 26914923; 34828401; 39605873
Review for gene: CYP2U1 was set to GREEN
Added comment: In some families, it appears visual symptoms may present before spasticity/neurological phenotype.

PMID: 26914923 - Three patients from one family, where visual issues (pigmentary degenerative maculopathy) presented before spasticity. Biallelic loss of function variant identified

PMID: 34828401 - Patient presenting with bilateral progressive visual loss and photophobia. Biallelic loss of function variant identified

PMID: 39605873 - Two sibs with compound heterozygous variants. One had manifest neurological abnormalities since early childhood; the second had no neurological abnormalities. Both had opthalmological abnormalities
Sources: Literature
Holoprosencephaly - NOT chromosomal v5.3 DISP1 Nour Elkhateeb reviewed gene: DISP1: Rating: ; Mode of pathogenicity: None; Publications: 38529886; Phenotypes: holoprosencephaly; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.23 MRPL49 Sarah Leigh Classified gene: MRPL49 as Amber List (moderate evidence)
Intellectual disability v9.23 MRPL49 Sarah Leigh Gene: mrpl49 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.3 MRPL49 Sarah Leigh changed review comment from: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature; to: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant, and families F4 & F5 (with the same MRPL variant) although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature
Intellectual disability v9.22 MRPL49 Sarah Leigh changed review comment from: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature; to: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant, and families F4 & F5 (with the same MRPL variant) although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature
Monogenic hearing loss v5.3 MRPL49 Sarah Leigh changed review comment from: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature; to: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant, and families F4 & F5 (with the same MRPL variant) although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature
Monogenic hearing loss v5.3 MRPL49 Sarah Leigh Tag Q2_25_expert_review tag was added to gene: MRPL49.
Mitochondrial disorders v9.3 MRPL49 Sarah Leigh Classified gene: MRPL49 as Amber List (moderate evidence)
Mitochondrial disorders v9.3 MRPL49 Sarah Leigh Gene: mrpl49 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.22 MRPL49 Sarah Leigh Marked gene: MRPL49 as ready
Intellectual disability v9.22 MRPL49 Sarah Leigh Gene: mrpl49 has been classified as Red List (Low Evidence).
Monogenic hearing loss v5.3 MRPL49 Sarah Leigh Classified gene: MRPL49 as Amber List (moderate evidence)
Monogenic hearing loss v5.3 MRPL49 Sarah Leigh Gene: mrpl49 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.2 MRPL49 Sarah Leigh gene: MRPL49 was added
gene: MRPL49 was added to Monogenic hearing loss. Sources: Literature
Q2_25_ promote_green tags were added to gene: MRPL49.
Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL49 were set to 40043708
Phenotypes for gene: MRPL49 were set to Combined oxidative phosphorylation deficiency 60, OMIM:621195; combined oxidative phosphorylation deficiency, MONDO:0000732
Review for gene: MRPL49 was set to GREEN
Added comment: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature
Mitochondrial disorders v9.2 MRPL49 Sarah Leigh gene: MRPL49 was added
gene: MRPL49 was added to Mitochondrial disorders. Sources: Literature
Q2_25_ promote_green tags were added to gene: MRPL49.
Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL49 were set to 40043708
Phenotypes for gene: MRPL49 were set to Combined oxidative phosphorylation deficiency 60, OMIM:621195; combined oxidative phosphorylation deficiency, MONDO:0000732
Review for gene: MRPL49 was set to GREEN
Added comment: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature
Intellectual disability v9.22 MRPL49 Sarah Leigh gene: MRPL49 was added
gene: MRPL49 was added to Intellectual disability. Sources: Literature
Q2_25_ promote_green tags were added to gene: MRPL49.
Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL49 were set to 40043708
Phenotypes for gene: MRPL49 were set to Combined oxidative phosphorylation deficiency 60, OMIM:621195; combined oxidative phosphorylation deficiency, MONDO:0000732
Review for gene: MRPL49 was set to GREEN
Added comment: Four biallelic MRPL variants have been seen in nine families with Combined oxidative phosphorylation deficiency 60 (OMIM:621195)(PMID: 40043708).
Families F1 & F2 shared a haplotype and the same MRPL variant and families F4 & F5, with the same MRPL variant, although not apparently related, came from the same village. Intellectual disability was apparent in all nine families (mild in one family), primary ovarian insufficiency was seen in 4/5 affected females and bilateral sensorineural hearing loss was evident in 6/9 families (PMID: 40043708)
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.11 SRP72 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: SRP72.
Tag Q2_25_expert_review tag was added to gene: SRP72.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.11 SRP72 Sarah Leigh Added comment: Comment on phenotypes: Familial MDS/AML;inherited bone marrow failure syndromes (IBMFS);congenital neutropenia;Shwachman-Diamond syndrome
Primary immunodeficiency or monogenic inflammatory bowel disease v8.11 SRP72 Sarah Leigh Phenotypes for gene: SRP72 were changed from Familial MDS/AML; inherited bone marrow failure syndromes (IBMFS); congenital neutropenia; Shwachman-Diamond syndrome to Bone marrow failure syndrome 1, OMIM:614675; autosomal dominant aplasia and myelodysplasia, MONDO:0013851
Primary immunodeficiency or monogenic inflammatory bowel disease v8.10 SRP72 Sarah Leigh Publications for gene: SRP72 were set to 32098966
Primary immunodeficiency or monogenic inflammatory bowel disease v8.9 SRP72 Sarah Leigh reviewed gene: SRP72: Rating: GREEN; Mode of pathogenicity: None; Publications: 22541560, 29146883; Phenotypes: Bone marrow failure syndrome 1, OMIM:614675, autosomal dominant aplasia and myelodysplasia, MONDO:0013851; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v8.9 SRP72 Sarah Leigh Classified gene: SRP72 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.9 SRP72 Sarah Leigh Gene: srp72 has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.17 FBXO22 Achchuthan Shanmugasundram changed review comment from: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease. Intrauterine growth restriction was reported in nine patients from eight families, and short stature was reported in eight patients from seven families.

This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.; to: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prominent prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous germline FBXO22 variants with loss-of-function effects segregating with the disease. Intrauterine growth restriction was reported in 11 patients from ten families, and short stature was reported in ten patients from nine families.

This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.
Haematological malignancies cancer susceptibility v4.24 SH2B3 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SH2B3.
Thrombocythaemia v1.6 SH2B3 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SH2B3.
Hereditary Erythrocytosis v2.13 SH2B3 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SH2B3.
Thrombocythaemia v1.6 SH2B3 Sarah Leigh Added comment: Comment on publications: https://doi.org/10.1182/blood-2024-210339 does not have a PMID number yet
Thrombocythaemia v1.6 SH2B3 Sarah Leigh Publications for gene: SH2B3 were set to
Thrombocythaemia v1.5 SH2B3 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: SH2B3.
Tag Q2_25_ NHS_review tag was added to gene: SH2B3.
Thrombocythaemia v1.5 SH2B3 Sarah Leigh reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28484264, 27237057, 23908464; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Haematological malignancies cancer susceptibility v4.24 SH2B3 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: SH2B3.
Haematological malignancies cancer susceptibility v4.24 SH2B3 Sarah Leigh reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28484264, 27237057, 23908464; Phenotypes: SH2B3 associated susceptibility to acute lymphoblastic leukemia, SH2B3 associated susceptibility to myeloproliferative neoplasms; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.21 FBXO22 Achchuthan Shanmugasundram changed review comment from: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease. Intellectual disability was reported in six patients from five families.

This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.; to: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prominent prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous germline FBXO22 variants with loss-of-function effects segregating with the disease. Intellectual disability was reported in seven patients from six families.

This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.
Haematological malignancies cancer susceptibility v4.24 SH2B3 Sarah Leigh Publications for gene: SH2B3 were set to 27881370; 23908464; 27913496; 39316992; 28484264; 27237057
Haematological malignancies cancer susceptibility v4.23 SH2B3 Sarah Leigh Publications for gene: SH2B3 were set to 27881370; 23908464; 27913496; 39316992; 28484264
Haematological malignancies cancer susceptibility v4.22 SH2B3 Sarah Leigh Publications for gene: SH2B3 were set to 27881370; 23908464; 27913496; 39316992
Haematological malignancies cancer susceptibility v4.21 SH2B3 Sarah Leigh Publications for gene: SH2B3 were set to 27881370; 23908464; 27913496
Haematological malignancies cancer susceptibility v4.20 SH2B3 Sarah Leigh Publications for gene: SH2B3 were set to 27881370; 23908464
Haematological malignancies cancer susceptibility v4.19 NAPRT Sarah Leigh edited their review of gene: NAPRT: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Haematological malignancies cancer susceptibility v4.19 NAPRT Sarah Leigh Mode of inheritance for gene: NAPRT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Haematological malignancies cancer susceptibility v4.18 NAPRT Sarah Leigh edited their review of gene: NAPRT: Added comment: Two monoallelic NAPRT variants have been reported in two unrelated cases with myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML)(PMID: 32098966; https://doi.org/10.1182/blood.V122.21.2803.2803). This is insufficient evidence to warrant a green gene rating.; Changed rating: AMBER; Changed phenotypes to: myelodysplastic syndrome (MDS), acute myeloid leukemia (AML); Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Haematological malignancies cancer susceptibility v4.18 NAPRT Sarah Leigh Mode of inheritance for gene: NAPRT was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Haematological malignancies cancer susceptibility v4.17 NAPRT Sarah Leigh Classified gene: NAPRT as Amber List (moderate evidence)
Haematological malignancies cancer susceptibility v4.17 NAPRT Sarah Leigh Gene: naprt has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.21 RAB3A Sarah Leigh changed review comment from: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood. This gene is appropriate for the Hereditary ataxia with onset in adulthood panel as PMID: 40166812 states "The median age at onset was 26.5 (interquartile range (IQR) 22–32) with gait ataxia as the first symptom in all probands.", In addition, the authors also present supportive functional studies.; to: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood.

The neurodevelopmental disorder associated with variants towards the 3' end of the gene: (NM_002866.5) c.565G>T, p.(Glu189*) and c.628C>T, p.(Gln210*), included global developmental delay and learning disability (PMID: 40166812, table S4).

In addition, the authors also present supportive functional studies for the RAB3A variants.
Intellectual disability v9.21 RAB3A Sarah Leigh edited their review of gene: RAB3A: Changed rating: AMBER
Intellectual disability v9.21 RAB3A Sarah Leigh Tag Q2_25_ promote_green was removed from gene: RAB3A.
Tag Q2_25_ NHS_review was removed from gene: RAB3A.
Intellectual disability v9.21 RAB3A Sarah Leigh Entity copied from Hereditary ataxia with onset in adulthood v8.5
Intellectual disability v9.21 RAB3A Sarah Leigh gene: RAB3A was added
gene: RAB3A was added to Intellectual disability. Sources: Research,Expert Review Amber
Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: RAB3A.
Mode of inheritance for gene: RAB3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB3A were set to 36928819; 40166812
Phenotypes for gene: RAB3A were set to RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay
Penetrance for gene: RAB3A were set to Complete
Monogenic short stature v1.17 FBXO22 Achchuthan Shanmugasundram Tag Q2_25_ NHS_review was removed from gene: FBXO22.
Monogenic short stature v1.17 FBXO22 Achchuthan Shanmugasundram changed review comment from: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease. Intellectual disability was reported in six patients from five families.

This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.; to: As reviewed by Julia Baptista, PMID:40215970 reported 16 cases (15 affected children and one foetus) from 14 unrelated families presenting with a pleiotropic syndrome with prenatal onset growth restriction and notable neurodevelopmental delay. They were identified with four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease. Intrauterine growth restriction was reported in nine patients from eight families, and short stature was reported in eight patients from seven families.

This gene has been associated with relevant phenotypes in OMIM (MIM #621184), but not yet in Gene2Phenotype.
Monogenic short stature v1.17 FBXO22 Achchuthan Shanmugasundram Entity copied from Intellectual disability v9.20
Monogenic short stature v1.17 FBXO22 Achchuthan Shanmugasundram gene: FBXO22 was added
gene: FBXO22 was added to Monogenic short stature. Sources: Literature,Expert Review Amber
Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: FBXO22.
Mode of inheritance for gene: FBXO22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXO22 were set to 40215970
Phenotypes for gene: FBXO22 were set to Tayoun-Maawali syndrome, OMIM:621184
Intellectual disability v9.20 FBXO22 Achchuthan Shanmugasundram Classified gene: FBXO22 as Amber List (moderate evidence)
Intellectual disability v9.20 FBXO22 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v9.20 FBXO22 Achchuthan Shanmugasundram Gene: fbxo22 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.19 FBXO22 Achchuthan Shanmugasundram Phenotypes for gene: FBXO22 were changed from neurodevelopmental delay; malformations; OMIM# 621184 to Tayoun-Maawali syndrome, OMIM:621184
Intellectual disability v9.18 FBXO22 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: FBXO22.
Tag Q2_25_ NHS_review tag was added to gene: FBXO22.
Intellectual disability v9.18 FBXO22 Achchuthan Shanmugasundram reviewed gene: FBXO22: Rating: GREEN; Mode of pathogenicity: None; Publications: 40215970; Phenotypes: Tayoun-Maawali syndrome, OMIM:621184; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v4.4 CCER2 Achchuthan Shanmugasundram Classified gene: CCER2 as Amber List (moderate evidence)
Cerebral vascular malformations v4.4 CCER2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexandra Njegic, PMID:27717682 reported the identification of CCER2 variants in two pedigrees with Moyamoya disease. One of the monozygotic twins from family 2 with the missense variant was unaffected suggesting reduced penetrance.

Although CCER2 variants were identified in three of 135 MMD probands additionally sequenced, two of them had RNF213 p.Arg4810Lys founder variant, and one had Graves disease.

In silicon functional analysis predicts that these variants promote aggregation or oligomerization of their protein product.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

This gene should be rated amber with current evidence.
Cerebral vascular malformations v4.4 CCER2 Achchuthan Shanmugasundram Gene: ccer2 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v4.3 CCER2 Achchuthan Shanmugasundram Phenotypes for gene: CCER2 were changed from Moyamoya Disease to Moyamoya Disease, MONDO:0016820
Cerebral vascular malformations v4.2 CCER2 Achchuthan Shanmugasundram reviewed gene: CCER2: Rating: AMBER; Mode of pathogenicity: None; Publications: 27717682; Phenotypes: Moyamoya Disease, MONDO:0016820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe early-onset obesity v5.4 GNB1 Achchuthan Shanmugasundram Classified gene: GNB1 as Amber List (moderate evidence)
Severe early-onset obesity v5.4 GNB1 Achchuthan Shanmugasundram Gene: gnb1 has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v5.3 GNB1 Achchuthan Shanmugasundram changed review comment from: PMID:38596856 reported three unrelated cases reported with either splicing or truncating variants in GNB1 gene and obesity. Although two of them were reported to start gain weight before 5 years of age, there were no information on their weight or BMI at onset. Hence, we cannot determine the severity of obesity at onset. The third case was reported to have obesity around 9 years of age.

This study also reviewed previously published cases, where two cases were reported with early-onset obesity (<5 years). However, not much information was available to ascertain the severity.

As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf), the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years. Hence, this gene should be rated amber with the current evidence.; to: PMID:38596856 reported three unrelated cases reported with either splicing or truncating variants in GNB1 gene and obesity. Although two of them were reported to start gain weight before 5 years of age, there were no information on their weight or BMI at onset. Hence, we cannot determine the severity of obesity at onset. The third case was reported to have obesity around 9 years of age.

This study also reviewed previously published cases, where two cases were reported with early-onset obesity (<5 years). However, complete information was not available to ascertain the severity.

As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf), the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years. Hence, this gene should be rated amber with the current evidence.
Severe early-onset obesity v5.3 GNB1 Achchuthan Shanmugasundram edited their review of gene: GNB1: Added comment: PMID:38596856 reported three unrelated cases reported with either splicing or truncating variants in GNB1 gene and obesity. Although two of them were reported to start gain weight before 5 years of age, there were no information on their weight or BMI at onset. Hence, we cannot determine the severity of obesity at onset. The third case was reported to have obesity around 9 years of age.

This study also reviewed previously published cases, where two cases were reported with early-onset obesity (<5 years). However, not much information was available to ascertain the severity.

As per the eligibility criteria on the National Genomic Test Directory (https://www.england.nhs.uk/wp-content/uploads/2018/08/rare-inherited-disease-eligibility-criteria-v8.0.pdf), the patients should have BMI more than 3 standard deviations above the mean, with onset before the age of 5 years. Hence, this gene should be rated amber with the current evidence.; Changed rating: AMBER
Severe early-onset obesity v5.3 GNB1 Achchuthan Shanmugasundram Publications for gene: GNB1 were set to
Severe early-onset obesity v5.2 GNB1 Achchuthan Shanmugasundram Phenotypes for gene: GNB1 were changed from PMID: 38596856 to Obesity, HP:0001513
Severe early-onset obesity v5.1 GNB1 Achchuthan Shanmugasundram reviewed gene: GNB1: Rating: RED; Mode of pathogenicity: None; Publications: 38596856; Phenotypes: Obesity, HP:0001513; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset hereditary spastic paraplegia v8.1 ATL1 Cassandra Smith reviewed gene: ATL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24473461, 26888483, 37927245, 39003427; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Structural eye disease v4.9 CYP1B1 Arina Puzriakova Phenotypes for gene: CYP1B1 were changed from Primary Congenital Glaucoma; Peters anomaly, 604229; Glaucoma 3, Primary Congenital, A; Glaucoma 3, Primary Congenital, A, GLC3A, 231300; Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset; GLC3A; primary congenital glaucoma; 231300 to Anterior segment dysgenesis 6, multiple subtypes, OMIML617315; Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset, OMIM:231300; Primary Congenital Glaucoma
Autoinflammatory disorders v2.5 COPA Arina Puzriakova Classified gene: COPA as Amber List (moderate evidence)
Autoinflammatory disorders v2.5 COPA Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Autoinflammatory disorders v2.5 COPA Arina Puzriakova Gene: copa has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.4 COPA Arina Puzriakova gene: COPA was added
gene: COPA was added to Autoinflammatory disorders. Sources: Literature
Q2_25_ promote_green tags were added to gene: COPA.
Mode of inheritance for gene: COPA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COPA were set to 25894502; 31455335; 38175705
Phenotypes for gene: COPA were set to {Autoinflammation and autoimmunity, systemic, with immune dysregulation}, OMIM:616414; COPA syndrome
Review for gene: COPA was set to GREEN
Added comment: Heterozygous variants in the COPA gene cause an autoinflammatory disorder that affects multiple organ systems. Affected individuals usually present in the first decade of life with variable features including interstitial lung disease with or without pulmonary hemorrhage, inflammatory arthritis, recurrent infections, and renal disease. Laboratory studies show evidence of systemic inflammation.

At least 9 unrelated families with more than 20 affected individuals have been reported in the literature (PMIDs: PMID: 25894502; 31455335; 38175705).

Variant hotspots include the WD40 domain and the C-terminal domain of the COPA protein.
Sources: Literature
Bardet Biedl syndrome v2.4 IFT57 Krista Bukele gene: IFT57 was added
gene: IFT57 was added to Bardet Biedl syndrome. Sources: Literature
Mode of inheritance for gene: IFT57 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT57 were set to PMID: 40273360
Phenotypes for gene: IFT57 were set to Bardet-Biedl syndrome
Penetrance for gene: IFT57 were set to unknown
Review for gene: IFT57 was set to AMBER
Added comment: PMID: 40273360 described one case with Bardet-Biedl syndrome and biallelic variant in IFT57 with some functional evidence.
Sources: Literature
Haematological malignancies cancer susceptibility v4.16 NAPRT Sarah Leigh Added comment: Comment on publications: https://doi.org/10.1182/blood.V122.21.2803.2803 there is no PMID for this article
Haematological malignancies cancer susceptibility v4.16 NAPRT Sarah Leigh Publications for gene: NAPRT were set to 32098966
Haematological malignancies cancer susceptibility v4.15 DNAH9 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: DNAH9.
Haematological malignancies cancer susceptibility v4.15 DNAH9 Sarah Leigh reviewed gene: DNAH9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Haematological malignancies cancer susceptibility v4.15 DNAH9 Sarah Leigh Publications for gene: DNAH9 were set to 32098966; 26492932
Haematological malignancies cancer susceptibility v4.14 DNAH9 Sarah Leigh Publications for gene: DNAH9 were set to 32098966
Haematological malignancies cancer susceptibility v4.13 DNAH9 Sarah Leigh Classified gene: DNAH9 as Amber List (moderate evidence)
Haematological malignancies cancer susceptibility v4.13 DNAH9 Sarah Leigh Gene: dnah9 has been classified as Amber List (Moderate Evidence).
Haematological malignancies cancer susceptibility v4.12 DHX34 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: DHX34.
Haematological malignancies cancer susceptibility v4.12 DHX34 Sarah Leigh reviewed gene: DHX34: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Haematological malignancies cancer susceptibility v4.12 DHX34 Sarah Leigh Classified gene: DHX34 as Amber List (moderate evidence)
Haematological malignancies cancer susceptibility v4.12 DHX34 Sarah Leigh Gene: dhx34 has been classified as Amber List (Moderate Evidence).
Haematological malignancies cancer susceptibility v4.11 DHX34 Sarah Leigh Phenotypes for gene: DHX34 were changed from Thrombocytopenia; Neutropenia; Pancytopenia; AML to myelodysplastic syndrome; acute myeloid leukemia
Haematological malignancies cancer susceptibility v4.10 ADA Sarah Leigh Phenotypes for gene: ADA were changed from severe combined immunodeficiency to Severe combined immunodeficiency due to ADA deficiency, OMIM: 102700
Haematological malignancies cancer susceptibility v4.9 ADA Sarah Leigh Classified gene: ADA as Amber List (moderate evidence)
Haematological malignancies cancer susceptibility v4.9 ADA Sarah Leigh Gene: ada has been classified as Amber List (Moderate Evidence).
Haematological malignancies cancer susceptibility v4.8 ADA Sarah Leigh reviewed gene: ADA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Haematological malignancies cancer susceptibility v4.8 TCF3 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: TCF3.
Tag Q2_25_expert_review tag was added to gene: TCF3.
Haematological malignancies cancer susceptibility v4.8 TCF3 Sarah Leigh reviewed gene: TCF3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: B-cell acute lymphoblastic leukemia, MONDO:0004947; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v8.8 COPA Arina Puzriakova Publications for gene: COPA were set to 28956095; 25894502; 29137621
Primary immunodeficiency or monogenic inflammatory bowel disease v8.7 COPA Arina Puzriakova Phenotypes for gene: COPA were changed from Autoimmune inflammatoy arthritis and interstial lung disease, 616414; Autoimmune interstitial lung disease-arthritis syndrome; COPA syndrome; Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production; Autoinflammatory Disorders to {Autoinflammation and autoimmunity, systemic, with immune dysregulation}, OMIM:616414
COVID-19 research v1.143 COPA Arina Puzriakova Phenotypes for gene: COPA were changed from Autoimmune interstitial lung disease-arthritis syndrome; Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production; Autoinflammatory Disorders; Autoimmune inflammatoy arthritis and interstial lung disease, 616414; COPA syndrome to {Autoinflammation and autoimmunity, systemic, with immune dysregulation}, OMIM:616414
Intellectual disability v9.18 SMARCA1 Sarah Leigh Phenotypes for gene: SMARCA1 were changed from Coffin-Siris Syndrome; ORPHA1465 to X-linked intellectual disability, MONDO:0100284
Intellectual disability v9.17 SMARCA1 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: SMARCA1.
Intellectual disability v9.17 SMARCA1 Sarah Leigh Classified gene: SMARCA1 as Amber List (moderate evidence)
Intellectual disability v9.17 SMARCA1 Sarah Leigh Gene: smarca1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.16 SMARCA1 Sarah Leigh reviewed gene: SMARCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479843, 27457812, 33057194, 40316778; Phenotypes: X-linked intellectual disability, MONDO:0100284; Mode of inheritance: None
Intellectual disability v9.16 SMARCA1 Sarah Leigh Publications for gene: SMARCA1 were set to 26539891; 26740508
Retinal disorders v8.4 RBP3 Arina Puzriakova Phenotypes for gene: RBP3 were changed from Retinitis pigmentosa 66 , OMIM:615233 to Retinitis pigmentosa 66, OMIM:615233
Retinal disorders v8.3 RBP3 Arina Puzriakova Publications for gene: RBP3 were set to Review of the literature from Stephanie Barton - Arno et al (2015) Lack of Interphotoreceptor Retinoid Binding Protein Caused by Homozygous Mutation of RBP3 Is Associated With High Myopia and Retinal Dystrophy. Invest Ophthalmol Vis Sci. Apr; 56(4):2358-65: Two novel homozygous nonsense mutations (c.1530T>A; p.Y510* and c.3454G>T; p.E1152*) in RBP3 were identified in four patients from two families. All four patients had a similar, unusual retinal dystrophy characterized by childhood onset high myopia, generalized rod and cone dysfunction, and an unremarkable fundus appearance. The FAF imaging showed multiple paracentral foci of low autofluorescence in one patient and patchy increased FAF in the region of the vascular arcades in another. The OCT showed loss of outer retinal bands over peripheral macular areas in all 4 cases; Abu-Safieh et al (2013) Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. Feb; 23(2):236-47; NM_002900.2 RBP3 :c.1162C>T; p.(Arg388*) identified in homozygous state in patient with sporadic RP; Li et al (2013) Secretory defect and cytotoxicity: the potential disease mechanisms for the retinitis pigmentosa (RP)-associated interphotoreceptor retinoid-binding protein (IRBP). J Biol Chem. Apr 19; 288(16):11395-406: Functional studies to assess pathogenicity of a missense change, D1080N, that was identified in a homozygous state in a patient with ARRP by Den Hollander et al 2009. The mutation abolished IRBP secretion and induced endoplasmic reticulum stress by forming insoluble IRBP-containing complexes via disulfide bonds. Conclude that Loss of normal function and gain of cytotoxic function are the likely mechanisms for retinal degeneration.
Retinal disorders v8.2 RBP3 Arina Puzriakova Phenotypes for gene: RBP3 were changed from Eye Disorders; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa; ?Retinitis pigmentosa 66, 615233 to Retinitis pigmentosa 66 , OMIM:615233
Ectodermal dysplasia v4.4 TWIST2 Arina Puzriakova Classified gene: TWIST2 as Amber List (moderate evidence)
Ectodermal dysplasia v4.4 TWIST2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Ectodermal dysplasia v4.4 TWIST2 Arina Puzriakova Gene: twist2 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v4.3 TWIST2 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: TWIST2.
Ectodermal dysplasia v4.3 TWIST2 Arina Puzriakova edited their review of gene: TWIST2: Changed phenotypes to: Ablepharon-macrostomia syndrome, OMIM:200110 (AD), Barber-Say syndrome, OMIM:209885 (AD), Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR)
Ectodermal dysplasia v4.3 TWIST2 Arina Puzriakova edited their review of gene: TWIST2: Changed rating: GREEN
Ectodermal dysplasia v4.3 TWIST2 Arina Puzriakova edited their review of gene: TWIST2: Added comment: This gene is associated with multiple overlapping phenotypes which could be considered as types of ectodermal dysplasia:

- Ablepharon-macrostomia syndrome, OMIM:200110 (AD) - sparse hair, redundant skin, facial dysmorphism

- Barber-Say syndrome, OMIM:209885 (AD) - hypertrichosis, sparse lashes, skin hyperlaxity and redundancy, facial dysmorphism

- Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR) - sparse hair, distichiasis and/or absent eyelashes, redundant skin, bitemporal skin lesions, facial dysmorphism; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ectodermal dysplasia v4.3 TWIST2 Arina Puzriakova changed review comment from: Comment on mode of inheritance: TWIST2 is associated with two phenotypes which could be relevant to this panel - Ablepharon-macrostomia syndrome, OMIM:200110 (AD) and Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR). Therefore setting MOI to both mono- and biallelic.; to: Comment on mode of inheritance: TWIST2 is associated with multiple phenotypes which could be relevant to this panel - Ablepharon-macrostomia syndrome, OMIM:200110 (AD), Barber-Say syndrome, OMIM:209885 (AD) and Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR). Therefore setting MOI to both mono- and biallelic.
Ectodermal dysplasia v4.3 TWIST2 Arina Puzriakova Phenotypes for gene: TWIST2 were changed from Focal facial dermal dysplasia 3, Setleis type to Ablepharon-macrostomia syndrome, OMIM:200110 (AD); Barber-Say syndrome, OMIM:209885 (AD); Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR)
Ectodermal dysplasia v4.2 TWIST2 Arina Puzriakova Added comment: Comment on mode of inheritance: TWIST2 is associated with two phenotypes which could be relevant to this panel - Ablepharon-macrostomia syndrome, OMIM:200110 (AD) and Focal facial dermal dysplasia 3, Setleis type, OMIM:227260 (AR). Therefore setting MOI to both mono- and biallelic.
Ectodermal dysplasia v4.2 TWIST2 Arina Puzriakova Mode of inheritance for gene: TWIST2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Breast cancer pertinent cancer susceptibility v2.13 PTEN Arina Puzriakova Classified gene: PTEN as Red List (low evidence)
Breast cancer pertinent cancer susceptibility v2.13 PTEN Arina Puzriakova Added comment: Comment on list classification: Germline PTEN variants confer up to 85% lifetime risk of female breast cancer. Inclusion on this panel should therefore be reviewed by the expert group at the next GMS panel update.
Breast cancer pertinent cancer susceptibility v2.13 PTEN Arina Puzriakova Gene: pten has been classified as Red List (Low Evidence).
Breast cancer pertinent cancer susceptibility v2.12 PTEN Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: PTEN.
Tag Q2_25_expert_review tag was added to gene: PTEN.
Intellectual disability v9.15 ATM Arina Puzriakova changed review comment from: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel.

Biallelic variants in the ATM gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration rather than primary ID that is a hallmark of the disorder.; to: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel.

Biallelic variants in the ATM gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline which is secondary to neurodegeneration rather than a primary ID that is a hallmark of the disorder.
Intellectual disability v9.15 ATM Arina Puzriakova changed review comment from: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel.

Biallelic variants in this gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration.; to: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel.

Biallelic variants in the ATM gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration rather than primary ID that is a hallmark of the disorder.
Intellectual disability v9.15 ATM Arina Puzriakova Classified gene: ATM as Green List (high evidence)
Intellectual disability v9.15 ATM Arina Puzriakova Added comment: Comment on list classification: Tagged for expert review to determine if this Green gene should be demoted on this panel.

Biallelic variants in this gene are associated with Ataxia-telangiectasia, an early-onset progressive cerebellar ataxia which comprises progressive neurologic degeneration, oculocutaneous telangiectasias, sinopulmonary infection, and malignancies. Some patients can display mild cognitive impairment and learning difficulties, but this reflects cognitive decline secondary to neurodegeneration.
Intellectual disability v9.15 ATM Arina Puzriakova Gene: atm has been classified as Green List (High Evidence).
Intellectual disability v9.14 ATM Arina Puzriakova Tag Q2_25_ demote_red tag was added to gene: ATM.
Tag Q2_25_expert_review tag was added to gene: ATM.
Intellectual disability v9.14 MAP4K4 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: MAP4K4.
Intellectual disability v9.14 MAP4K4 Arina Puzriakova Classified gene: MAP4K4 as Amber List (moderate evidence)
Intellectual disability v9.14 MAP4K4 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene as Green at the next GMS panel update - at least 26 individuals from 21 families reported with Rasopathy-like phenotype (PMID: 37126546). Clinical presentation is varied, but most display symptoms of neurodevelopmental conditions with features overlapping those observed in patients with RASopathies. DD/ID was one of the most common features (ID reported in 8/21 cases).
Intellectual disability v9.14 MAP4K4 Arina Puzriakova Gene: map4k4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.13 MAP4K4 Arina Puzriakova Entity copied from DDG2P v6.1
Intellectual disability v9.13 MAP4K4 Arina Puzriakova gene: MAP4K4 was added
gene: MAP4K4 was added to Intellectual disability. Sources: Literature,Expert Review Green,DD-Gene2Phenotype
gene-checked tags were added to gene: MAP4K4.
Mode of inheritance for gene: MAP4K4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAP4K4 were set to 36469137; 28518170; 37126546; 37126546
Phenotypes for gene: MAP4K4 were set to MAP4K4-related neurodevelopmental disorder with/without congenital anomalies; multiple congenital anomalies; neurodevelopmental differences
Mode of pathogenicity for gene: MAP4K4 was set to Other
RASopathies v1.83 MAP4K4 Arina Puzriakova Tag gene-checked tag was added to gene: MAP4K4.
RASopathies v1.83 MAP4K4 Arina Puzriakova Publications for gene: MAP4K4 were set to PMID: 37126546
RASopathies v1.82 MAP4K4 Arina Puzriakova Classified gene: MAP4K4 as Green List (high evidence)
RASopathies v1.82 MAP4K4 Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence to rate as Green - at least 26 individuals from 21 families reported with Rasopathy-like phenotype (PMID: 37126546)
RASopathies v1.82 MAP4K4 Arina Puzriakova Gene: map4k4 has been classified as Green List (High Evidence).
Hereditary ataxia with onset in adulthood v8.5 RAB3A Sarah Leigh changed review comment from: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood. The authors also present supportive functional studies.; to: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood. This gene is appropriate for the Hereditary ataxia with onset in adulthood panel as PMID: 40166812 states "The median age at onset was 26.5 (interquartile range (IQR) 22–32) with gait ataxia as the first symptom in all probands.", In addition, the authors also present supportive functional studies.
Hereditary ataxia with onset in adulthood v8.5 RAB3A Sarah Leigh Entity copied from Ataxia and cerebellar anomalies - narrow panel v8.3
Hereditary ataxia with onset in adulthood v8.5 RAB3A Sarah Leigh gene: RAB3A was added
gene: RAB3A was added to Hereditary ataxia with onset in adulthood. Sources: Expert Review Amber,Research
Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: RAB3A.
Mode of inheritance for gene: RAB3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB3A were set to 36928819; 40166812
Phenotypes for gene: RAB3A were set to RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay
Penetrance for gene: RAB3A were set to Complete
Retinal disorders v8.1 RLBP1 Cassandra Smith reviewed gene: RLBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.1 RDH5 Cassandra Smith reviewed gene: RDH5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.1 KIAA1549 Cassandra Smith reviewed gene: KIAA1549: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v7.4 MAN2B2 Arina Puzriakova Classified gene: MAN2B2 as Amber List (moderate evidence)
Congenital disorders of glycosylation v7.4 MAN2B2 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel update.
Congenital disorders of glycosylation v7.4 MAN2B2 Arina Puzriakova Gene: man2b2 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v7.3 MAN2B2 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: MAN2B2.
Tag Q2_25_ NHS_review tag was added to gene: MAN2B2.
Likely inborn error of metabolism v8.5 MAN2B2 Arina Puzriakova Classified gene: MAN2B2 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.5 MAN2B2 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel update.
Likely inborn error of metabolism v8.5 MAN2B2 Arina Puzriakova Gene: man2b2 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v7.3 MAN2B2 Arina Puzriakova reviewed gene: MAN2B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38622837; Phenotypes: Congenital disorder of glycosylation type 1EE with or without immunodeficiency, OMIM:621140; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.4 MAN2B2 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: MAN2B2.
Tag Q2_25_ NHS_review tag was added to gene: MAN2B2.
Likely inborn error of metabolism v8.4 MAN2B2 Arina Puzriakova reviewed gene: MAN2B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38622837; Phenotypes: Congenital disorder of glycosylation type 1EE with or without immunodeficiency, OMIM:621140; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.6 MAN2B2 Arina Puzriakova Classified gene: MAN2B2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.6 MAN2B2 Arina Puzriakova Added comment: Comment on list classification: Upgrading to Amber as another patient has been identified with biallelic variants (c.384G>T; c.926T>A) in the MAN2B2 gene, who displayed immune dysregulation as part of the phenotype (PMID: 38622837)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.6 MAN2B2 Arina Puzriakova Gene: man2b2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.5 MAN2B2 Arina Puzriakova Publications for gene: MAN2B2 were set to 31775018
Likely inborn error of metabolism v8.4 MAN2B2 Arina Puzriakova Publications for gene: MAN2B2 were set to 31775018; 35637269
Congenital disorders of glycosylation v7.3 MAN2B2 Arina Puzriakova Publications for gene: MAN2B2 were set to 31775018; 35637269
Likely inborn error of metabolism v8.3 MAN2B2 Arina Puzriakova Phenotypes for gene: MAN2B2 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation type 1EE with or without immunodeficiency, OMIM:621140
Primary immunodeficiency or monogenic inflammatory bowel disease v8.4 MAN2B2 Arina Puzriakova Phenotypes for gene: MAN2B2 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation type 1EE with or without immunodeficiency, OMIM:621140
Congenital disorders of glycosylation v7.2 MAN2B2 Arina Puzriakova Phenotypes for gene: MAN2B2 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation type 1EE with or without immunodeficiency, OMIM:621140
Primary immunodeficiency or monogenic inflammatory bowel disease v8.3 AICDA Arina Puzriakova changed review comment from: Current literature strongly supports that heterozygous stop-gain variants are the primary variants linked to autosomal dominant forms of AICDA-related Hyper-IgM syndrome. These loss-of-function variants are well-documented to cause haploinsufficiency or a dominant-negative effect.

In contrast, missense variants lack robust evidence for pathogenicity in the context of dominant disease. Missense variants have only been reported in recessive cases, often with functional validation.

ClinGen only lists LOF variants associated with autosomal dominant form of Hyper-IgM syndrome Type 2 (https://search.clinicalgenome.org/CCID:004081).; to: Review based on feedback from Dr Julio Rodríguez López (Santiago Clinic Hospital CHUS, Spain):

Current literature strongly supports that heterozygous stop-gain variants are the primary variants linked to autosomal dominant forms of AICDA-related Hyper-IgM syndrome. These loss-of-function variants are well-documented to cause haploinsufficiency or a dominant-negative effect.

In contrast, missense variants lack robust evidence for pathogenicity in the context of dominant disease. Missense variants have only been reported in recessive cases, often with functional validation.

ClinGen only lists LOF variants associated with autosomal dominant form of Hyper-IgM syndrome Type 2 (https://search.clinicalgenome.org/CCID:004081).
Likely inborn error of metabolism v8.2 ARSG Sadaf Naz reviewed gene: ARSG: Rating: GREEN; Mode of pathogenicity: None; Publications: 29300381, 32455177, 33300174, 33629623, 34223797, 35226187; Phenotypes: Usher syndrome, type IV; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.12 SEL1L Achchuthan Shanmugasundram Classified gene: SEL1L as Amber List (moderate evidence)
Intellectual disability v9.12 SEL1L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Julia Baptista, there is sufficient evidence available (three unrelated families) for the association of this gene with intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.12 SEL1L Achchuthan Shanmugasundram Gene: sel1l has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.11 SEL1L Achchuthan Shanmugasundram changed review comment from: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia, leading to its exclusion from being causal for these patients.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.; to: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.
Intellectual disability v9.11 SEL1L Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SEL1L.
Tag Q2_25_ NHS_review tag was added to gene: SEL1L.
Intellectual disability v9.11 SEL1L Achchuthan Shanmugasundram Phenotypes for gene: SEL1L were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia, OMIM:621068; ?Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, OMIM:621067
Intellectual disability v9.10 SEL1L Achchuthan Shanmugasundram Publications for gene: SEL1L were set to 37943610, 37943617
Intellectual disability v9.9 SEL1L Achchuthan Shanmugasundram changed review comment from: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia (33), leading to its exclusion from being causal for these patients.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.; to: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia, leading to its exclusion from being causal for these patients.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.
Intellectual disability v9.9 SEL1L Achchuthan Shanmugasundram changed review comment from: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.; to: PMID:37943610 reported six patients from three unrelated families with a neurodevelopmental disorder involving developmental delay, intellectual disability, facial dysmorphisms, short stature, microcephaly and seizures. Five patients from two families (Saudi Arabian and Moroccan descent) were identified with homozygous SEL1L variants (p.(Gly585Asp) & p.(Met528Arg)), while an unrelated patient of Italian descent was identified with homozygous HRD1 variant. Although there are additional variants reported in Saudi Arabian patient, SEL1L variant was considered as the potential candidate due to its biological relevance as reported in previous studies in mice. The variants were hypomorphic and impaired endoplasmic reticulum (ER)-associated degradation.

PMID:37943617 reported the identification of a homozygous SEL1L variant (p.(Cys141Tyr)) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. All patients exhibited intellectual disability and were unable to speak words and sentences. Although variant in FAR2 gene was also identified in these patients, Sanger sequencing confirmed the segregation of the FAR2 variant with symptoms in patient 2 and FAR2 function is not linked to neurological disorder or agammaglobulinemia (33), leading to its exclusion from being causal for these patients.

This gene has been associated with relevant phenotypes in OMIM (MIMs #621067 & #621068), but not yet in Gene2Phenotype.
Intellectual disability v9.9 SEL1L Achchuthan Shanmugasundram reviewed gene: SEL1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 37943610, 37943617; Phenotypes: Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia, OMIM:621068, ?Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, OMIM:621067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3 JAG2 Achchuthan Shanmugasundram Classified gene: JAG2 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3 JAG2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Lauren Turton, there is sufficient evidence available (16 unrelated families) for the association of JAG2 with Limb-girdle muscular dystrophy-27 (MIM #619566). Hence, this gene should be promoted to green rating in the next GMS update.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.3 JAG2 Achchuthan Shanmugasundram Gene: jag2 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.2 JAG2 Achchuthan Shanmugasundram Phenotypes for gene: JAG2 were changed from Limb-girdle muscular dystrophy-27 (OMIM: 619566) to Muscular dystrophy, limb-girdle, autosomal recessive 27, OMIM:619566
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.1 JAG2 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: JAG2.
Tag Q2_25_ NHS_review tag was added to gene: JAG2.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.1 JAG2 Achchuthan Shanmugasundram reviewed gene: JAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33861953, 39121631, 39649397; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 27, OMIM:619566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.9 MECP2 Arina Puzriakova Phenotypes for gene: MECP2 were changed from Rett syndrome, 312750Mental retardation, X-linked, syndromic 13, 300055Rett syndrome, preserved speech variant, 312750Encephalopathy, neonatal severe, 300673{Autism susceptibility, X-linked 3}, 300496Angelman syndrome, 105830Mental retardation, X-linked syndromic, Lubs type, 300260; RETT SYNDROME (RTT)[ to Encephalopathy, neonatal severe, OMIM:300673; Intellectual developmental disorder, X-linked syndromic 13, OMIM:300055; Intellectual developmental disorder, X-linked syndromic, Lubs type, OMIM:300260; Rett syndrome, OMIM:312750; Rett syndrome, atypical, OMIM:312750; Rett syndrome, preserved speech variant, OMIM:312750
Intellectual disability v9.8 TAF2 Arina Puzriakova Phenotypes for gene: TAF2 were changed from Mental retardation, autosomal recessive 40, OMIM:615599 to Intellectual developmental disorder, autosomal recessive 40, OMIM:615599
Early onset or syndromic epilepsy v8.3 SYNGAP1 Arina Puzriakova Phenotypes for gene: SYNGAP1 were changed from Mental retardation, autosomal dominant 5 to Intellectual developmental disorder, autosomal dominant 5, OMIM:612621
Hereditary ataxia with onset in adulthood v8.4 SYNGAP1 Arina Puzriakova Phenotypes for gene: SYNGAP1 were changed from Autosomal dominant mental retardation 5, 612621 to Intellectual developmental disorder, autosomal dominant 5, OMIM:612621
Fetal anomalies v6.5 SYNGAP1 Arina Puzriakova Phenotypes for gene: SYNGAP1 were changed from EPILEPTIC ENCEPHALOPATHY; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 5 to Intellectual developmental disorder, autosomal dominant 5, OMIM:612621
Intellectual disability v9.7 SYNGAP1 Arina Puzriakova Phenotypes for gene: SYNGAP1 were changed from Mental retardation, autosomal dominant 5, 612621; EPILEPTIC ENCEPHALOPATHY to Intellectual developmental disorder, autosomal dominant 5, OMIM:612621
Cerebral vascular malformations v4.2 SIRT1 Arina Puzriakova Classified gene: SIRT1 as Red List (low evidence)
Cerebral vascular malformations v4.2 SIRT1 Arina Puzriakova Added comment: Comment on list classification: Rating Red as only a single case has been reported to date. Additional evidence is required before attributing causality.
Cerebral vascular malformations v4.2 SIRT1 Arina Puzriakova Gene: sirt1 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v7.2 EPB41L3 Arina Puzriakova Entity copied from Intellectual disability v9.6
White matter disorders and cerebral calcification - narrow panel v7.2 EPB41L3 Arina Puzriakova gene: EPB41L3 was added
gene: EPB41L3 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature,Expert Review Amber
Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: EPB41L3.
Mode of inheritance for gene: EPB41L3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPB41L3 were set to 39292993
Phenotypes for gene: EPB41L3 were set to Developmental disorder with seizures and myelination defects
Early onset or syndromic epilepsy v8.2 EPB41L3 Arina Puzriakova Entity copied from Intellectual disability v9.6
Early onset or syndromic epilepsy v8.2 EPB41L3 Arina Puzriakova gene: EPB41L3 was added
gene: EPB41L3 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: EPB41L3.
Mode of inheritance for gene: EPB41L3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPB41L3 were set to 39292993
Phenotypes for gene: EPB41L3 were set to Developmental disorder with seizures and myelination defects
Intellectual disability v9.6 EPB41L3 Arina Puzriakova Classified gene: EPB41L3 as Amber List (moderate evidence)
Intellectual disability v9.6 EPB41L3 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v9.6 EPB41L3 Arina Puzriakova Gene: epb41l3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.5 EPB41L3 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: EPB41L3.
Tag Q2_25_ NHS_review tag was added to gene: EPB41L3.
Intellectual disability v9.5 EPB41L3 Arina Puzriakova reviewed gene: EPB41L3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39292993; Phenotypes: Developmental disorder with seizures and myelination defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.5 EPB41L3 Arina Puzriakova Phenotypes for gene: EPB41L3 were changed from developmental delay; intellectual disability; seizures; hypotonia; neuroregression to Developmental disorder with seizures and myelination defects
Severe microcephaly v8.2 EEF1D Arina Puzriakova Entity copied from Intellectual disability v9.4
Severe microcephaly v8.2 EEF1D Arina Puzriakova gene: EEF1D was added
gene: EEF1D was added to Severe microcephaly. Sources: Expert Review Amber,Literature
Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: EEF1D.
Mode of inheritance for gene: EEF1D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EEF1D were set to 36576126; 30787422; 38083972; 28097321
Phenotypes for gene: EEF1D were set to Neurodevelopmental disorder with thin corpus callosum, hypotonia, and absent language, OMIM:621150
Intellectual disability v9.4 EEF1D Arina Puzriakova Phenotypes for gene: EEF1D were changed from Neurodevelopmental disorder; OMIM#621150 to Neurodevelopmental disorder with thin corpus callosum, hypotonia, and absent language, OMIM:621150
Intellectual disability v9.3 EEF1D Arina Puzriakova Classified gene: EEF1D as Amber List (moderate evidence)
Intellectual disability v9.3 EEF1D Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v9.3 EEF1D Arina Puzriakova Gene: eef1d has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.2 EEF1D Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: EEF1D.
Tag Q2_25_ NHS_review tag was added to gene: EEF1D.
Intellectual disability v9.2 EEF1D Arina Puzriakova reviewed gene: EEF1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 28097321, 30787422, 36576126, 38083972; Phenotypes: Neurodevelopmental disorder with thin corpus callosum, hypotonia, and absent language, OMIM:621150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Haematological malignancies cancer susceptibility v4.8 TCF3 Sarah Leigh Publications for gene: TCF3 were set to 36576946
Haematological malignancies cancer susceptibility v4.7 TCF3 Sarah Leigh Classified gene: TCF3 as Amber List (moderate evidence)
Haematological malignancies cancer susceptibility v4.7 TCF3 Sarah Leigh Gene: tcf3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.3 SLCO2A1 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SLCO2A1.
Tag Q2_25_expert_review tag was added to gene: SLCO2A1.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.3 SLCO2A1 Sarah Leigh reviewed gene: SLCO2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.3 SLCO2A1 Sarah Leigh Phenotypes for gene: SLCO2A1 were changed from Prostaglandin transporter deficiency to Hypertrophic osteoarthropathy, primary, autosomal recessive 2 OMIM:614441; hypertrophic osteoarthropathy, primary, autosomal recessive, 2, MONDO:0013756; Hypertrophic osteoarthropathy, primary, autosomal dominant, OMIM:167100; hypertrophic osteoarthropathy, primary, autosomal dominant, MONDO:0008172
Primary immunodeficiency or monogenic inflammatory bowel disease v8.2 SLCO2A1 Sarah Leigh Publications for gene: SLCO2A1 were set to 29313109
Skeletal dysplasia v8.4 SLCO2A1 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SLCO2A1.
Autosomal recessive primary hypertrophic osteoarthropathy v1.14 SLCO2A1 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SLCO2A1.
Tag Q2_25_expert_review tag was added to gene: SLCO2A1.
Autosomal recessive primary hypertrophic osteoarthropathy v1.14 SLCO2A1 Sarah Leigh Publications for gene: SLCO2A1 were set to
Skeletal dysplasia v8.4 SLCO2A1 Sarah Leigh edited their review of gene: SLCO2A1: Added comment: SLCO2A1 variants are associated with autosomal recessive and autosomal dominant forms of primary hypertrophic osteoarthropathy (OMIM:614441, OMIM:167100) in numerous cases (PMID:23509104; 27134495; 33852188; 22331663; 27134495).; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Autosomal recessive primary hypertrophic osteoarthropathy v1.13 SLCO2A1 Sarah Leigh reviewed gene: SLCO2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.4 C1orf127 Arina Puzriakova commented on gene: C1orf127: Added new-gene-name tag, new approved HGNC gene symbol for C1orf127 is CIROZ
Laterality disorders and isomerism v4.3 C1orf127 Arina Puzriakova commented on gene: C1orf127: Added new-gene-name tag, new approved HGNC gene symbol for C1orf127 is CIROZ
Fetal anomalies v6.4 C1orf127 Arina Puzriakova Tag new-gene-name tag was added to gene: C1orf127.
Laterality disorders and isomerism v4.3 C1orf127 Arina Puzriakova Tag new-gene-name tag was added to gene: C1orf127.
Fetal anomalies v6.4 C1orf127 Arina Puzriakova Classified gene: C1orf127 as Amber List (moderate evidence)
Fetal anomalies v6.4 C1orf127 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Fetal anomalies v6.4 C1orf127 Arina Puzriakova Gene: c1orf127 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v8.4 SLCO2A1 Sarah Leigh Publications for gene: SLCO2A1 were set to
Laterality disorders and isomerism v4.3 C1orf127 Arina Puzriakova Classified gene: C1orf127 as Amber List (moderate evidence)
Laterality disorders and isomerism v4.3 C1orf127 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Laterality disorders and isomerism v4.3 C1orf127 Arina Puzriakova Gene: c1orf127 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v4.2 C1orf127 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: C1orf127.
Tag Q2_25_ NHS_review tag was added to gene: C1orf127.
Fetal anomalies v6.3 C1orf127 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: C1orf127.
Tag Q2_25_ NHS_review tag was added to gene: C1orf127.
Fetal anomalies v6.3 C1orf127 Arina Puzriakova reviewed gene: C1orf127: Rating: GREEN; Mode of pathogenicity: None; Publications: 39753129; Phenotypes: Heterotaxy, visceral, 14, autosomal, OMIM:621080; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Laterality disorders and isomerism v4.2 C1orf127 Arina Puzriakova reviewed gene: C1orf127: Rating: GREEN; Mode of pathogenicity: None; Publications: 39753129; Phenotypes: Heterotaxy, visceral, 14, autosomal, OMIM:621080; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.3 C1orf127 Arina Puzriakova Phenotypes for gene: C1orf127 were changed from Heterotaxy to Heterotaxy, visceral, 14, autosomal, OMIM:621080
Laterality disorders and isomerism v4.2 C1orf127 Arina Puzriakova Phenotypes for gene: C1orf127 were changed from Heterotaxy to Heterotaxy, visceral, 14, autosomal, OMIM:621080
Skeletal dysplasia v8.3 SLCO2A1 Sarah Leigh Phenotypes for gene: SLCO2A1 were changed from Hypertrophic osteoarthropathy, primary, autosomal recessive 2 614441; Hypertrophic osteoarthropathy, primary, autosomal recessive 2 614441 to Hypertrophic osteoarthropathy, primary, autosomal recessive 2 OMIM:614441; hypertrophic osteoarthropathy, primary, autosomal recessive, 2, MONDO:0013756; Hypertrophic osteoarthropathy, primary, autosomal dominant, OMIM:167100; hypertrophic osteoarthropathy, primary, autosomal dominant, MONDO:0008172
Autosomal recessive primary hypertrophic osteoarthropathy v1.13 SLCO2A1 Sarah Leigh Phenotypes for gene: SLCO2A1 were changed from Hypertrophic osteoarthropathy, primary, autosomal recessive 2 OMIM:614441 to Hypertrophic osteoarthropathy, primary, autosomal recessive 2 OMIM:614441; hypertrophic osteoarthropathy, primary, autosomal recessive, 2, MONDO:0013756; Hypertrophic osteoarthropathy, primary, autosomal dominant, OMIM:167100; hypertrophic osteoarthropathy, primary, autosomal dominant, MONDO:0008172
Hereditary ataxia with onset in adulthood v8.3 NEU1 Arina Puzriakova Classified gene: NEU1 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v8.3 NEU1 Arina Puzriakova Added comment: Comment on list classification: Biallelic variants in the NEU1 gene are associated with Sialidosis (OMIM: 256550). Both Sialidosis Type I (milder, late-onset) and Sialidosis Type II (more severe, early-onset) can present with ataxia as part of a systemic neurological condition.

Overall there are sufficient unrelated cases to warrant inclusion on this panel.
Hereditary ataxia with onset in adulthood v8.3 NEU1 Arina Puzriakova Gene: neu1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.3 NEU1 Arina Puzriakova Classified gene: NEU1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.3 NEU1 Arina Puzriakova Added comment: Comment on list classification: Biallelic variants in the NEU1 gene are associated with Sialidosis (OMIM: 256550). Both Sialidosis Type I (milder, late-onset) and Sialidosis Type II (more severe, early-onset) can present with ataxia as part of a systemic neurological condition.

Overall there are sufficient unrelated cases to warrant inclusion on this panel.
Ataxia and cerebellar anomalies - narrow panel v8.3 NEU1 Arina Puzriakova Gene: neu1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.2 NEU1 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: NEU1.
Tag Q2_25_ NHS_review tag was added to gene: NEU1.
Hereditary ataxia with onset in adulthood v8.2 NEU1 Arina Puzriakova Tag Q2_25_ promote_green tag was added to gene: NEU1.
Tag Q2_25_ NHS_review tag was added to gene: NEU1.
Intellectual disability v9.2 NEU1 Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis, type I, 256550Sialidosis, type II, 256550; SIALIDOSIS (SIALIDOSIS) to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550
Hereditary ataxia with onset in adulthood v8.2 NEU1 Arina Puzriakova Phenotypes for gene: NEU1 were changed from Ataxia; myoclonus to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550; Ataxia; Myoclonus
Likely inborn error of metabolism v8.2 NEU1 Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis type II; Sialidosis, type I; Sialidosis (Oligosaccharidoses); Mucolipidosis, Type I; Sialidosis to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550; Mucolipidosis, Type I
Fetal anomalies v6.2 NEU1 Arina Puzriakova Phenotypes for gene: NEU1 were changed from SIALIDOSIS to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550
Undiagnosed metabolic disorders v1.629 NEU1 Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis (Oligosaccharidoses); Sialidosis; Sialidosis, type I; Sialidosis type II; Mucolipidosis, Type I to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550; Mucolipidosis, Type I
Skeletal dysplasia v8.2 NEU1 Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis, type II 256550; Sialidosis, type I 256550 to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550
Ataxia and cerebellar anomalies - narrow panel v8.2 NEU1 Arina Puzriakova Phenotypes for gene: NEU1 were changed from Ataxia; myoclonus to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550; Ataxia; Myoclonus
Fetal hydrops v1.89 NEU1 Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis, type I, 256550; Sialidosis, type II, 256550; Sialidosis; fetal hydrops; Hydrops fetalis (type II, congenital) to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550; fetal hydrops; Hydrops fetalis (type II, congenital)
Mucopolysaccharideosis, Gaucher, Fabry v1.3 NEU1 Arina Puzriakova Phenotypes for gene: NEU1 were changed from Sialidosis; Sialidosis, type I; Sialidosis type II; Mucolipidosis, Type I to Sialidosis, type I, OMIM:256550; Sialidosis, type II, OMIM:256550
Primary immunodeficiency or monogenic inflammatory bowel disease v8.1 AICDA Arina Puzriakova commented on gene: AICDA: Current literature strongly supports that heterozygous stop-gain variants are the primary variants linked to autosomal dominant forms of AICDA-related Hyper-IgM syndrome. These loss-of-function variants are well-documented to cause haploinsufficiency or a dominant-negative effect.

In contrast, missense variants lack robust evidence for pathogenicity in the context of dominant disease. Missense variants have only been reported in recessive cases, often with functional validation.

ClinGen only lists LOF variants associated with autosomal dominant form of Hyper-IgM syndrome Type 2 (https://search.clinicalgenome.org/CCID:004081).
Hereditary neuropathy v1.497 ARHGAP19 Shahryar Alavi gene: ARHGAP19 was added
gene: ARHGAP19 was added to Hereditary neuropathy. Sources: Research
Mode of inheritance for gene: ARHGAP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARHGAP19 were set to https://www.medrxiv.org/content/10.1101/2024.05.10.24306768v1
Phenotypes for gene: ARHGAP19 were set to neuropathy; Charcot-Marie-Tooth disease
Penetrance for gene: ARHGAP19 were set to Complete
Mode of pathogenicity for gene: ARHGAP19 was set to Other
Review for gene: ARHGAP19 was set to GREEN
Added comment: A comprehensive study on loss of function variants of the ARHGAP19 gene from several unrelated families shows that homozygous mutations cause early-onset motor-predominant neuropathy.
Biochemical assays revealed that GAP domain variants cause loss of protein function. Fruit fly and Zebrafish loss of function models also showed movement deficits.
RNA-Seq analysis confirmed downregulation of ARHGAP19 as well as cell cycle, motor and muscular cytoskeleton pathways in patients compared to controls.
The paper is under review.
Sources: Research
Unexplained young onset end-stage renal disease v12.8 Achchuthan Shanmugasundram Panel version 12.7 has been signed off on 2025-04-30
Unexplained death in infancy and sudden unexplained death in childhood v21.5 Achchuthan Shanmugasundram Panel version 21.4 has been signed off on 2025-04-30
Rare multisystem ciliopathy Super panel v21.2 Eleanor Williams Panel version 21.1 has been signed off on 2025-04-30
Hypotonic infant v44.5 Arina Puzriakova Panel version 44.4 has been signed off on 2025-04-30
Paediatric disorders v72.2 Eleanor Williams Panel version 72.1 has been signed off on 2025-04-30
Hereditary ataxia and cerebellar anomalies - childhood onset v22.2 Arina Puzriakova Panel version 22.1 has been signed off on 2025-04-30
Sudden unexplained death or survivors of a cardiac event v22.8 Achchuthan Shanmugasundram Panel version 22.7 has been signed off on 2025-04-30
Cystic renal disease v12.3 Arina Puzriakova Panel version 12.2 has been signed off on 2025-04-30
Childhood onset leukodystrophy v30.2 Arina Puzriakova Panel version 30.1 has been signed off on 2025-04-30
Other rare neuromuscular disorders v30.5 Eleanor Williams Panel version 30.4 has been signed off on 2025-04-30
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.3 Sarah Leigh Panel version 2.2 has been signed off on 2025-04-30
Haematuria v2.16 Sarah Leigh Panel version 2.15 has been signed off on 2025-04-30
Hereditary systemic amyloidosis v1.25 Sarah Leigh Panel version 1.24 has been signed off on 2025-04-30
PTEN Hamartoma Tumour Syndrome v1.3 Eleanor Williams Panel version 1.2 has been signed off on 2025-04-30
Distal myopathies v6.5 Sarah Leigh Panel version 6.4 has been signed off on 2025-04-30
Progressive cardiac conduction disease v2.11 Eleanor Williams Panel version 2.10 has been signed off on 2025-04-30
Paediatric motor neuronopathies v3.10 Eleanor Williams Panel version 3.9 has been signed off on 2025-04-30
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.7 Eleanor Williams Panel version 3.6 has been signed off on 2025-04-30
Long QT syndrome v3.11 Eleanor Williams Panel version 3.10 has been signed off on 2025-04-30
Paroxysmal central nervous system disorders v4.1 Eleanor Williams Panel version 4.0 has been signed off on 2025-04-30
Paroxysmal central nervous system disorders v4.0 Eleanor Williams promoted panel to version 4.0
Palmoplantar keratodermas v4.1 Eleanor Williams Panel version 4.0 has been signed off on 2025-04-30
Palmoplantar keratodermas v4.0 Eleanor Williams promoted panel to version 4.0
Paediatric pseudo-obstruction syndrome v2.1 Eleanor Williams Panel version 2.0 has been signed off on 2025-04-30
Paediatric pseudo-obstruction syndrome v2.0 Eleanor Williams promoted panel to version 2.0
Paediatric or syndromic cardiomyopathy v7.1 Eleanor Williams Panel version 7.0 has been signed off on 2025-04-30
Paediatric or syndromic cardiomyopathy v7.0 Eleanor Williams promoted panel to version 7.0
Paediatric disorders - additional genes v7.1 Eleanor Williams Panel version 7.0 has been signed off on 2025-04-30
Paediatric disorders - additional genes v7.0 Eleanor Williams promoted panel to version 7.0
Osteogenesis imperfecta v5.1 Eleanor Williams Panel version 5.0 has been signed off on 2025-04-30
Osteogenesis imperfecta v5.0 Eleanor Williams promoted panel to version 5.0
Optic neuropathy v5.1 Eleanor Williams Panel version 5.0 has been signed off on 2025-04-30
Optic neuropathy v5.0 Eleanor Williams promoted panel to version 5.0
Unexplained young onset end-stage renal disease - additional genes v1.2 Achchuthan Shanmugasundram Panel version 1.1 has been signed off on 2025-04-30
Tubulointerstitial kidney disease v3.6 Achchuthan Shanmugasundram Panel version 3.5 has been signed off on 2025-04-30
Ophthalmological ciliopathies v5.1 Eleanor Williams Panel version 5.0 has been signed off on 2025-04-30
Ophthalmological ciliopathies v5.0 Eleanor Williams promoted panel to version 5.0
Sickle cell, thalassaemia and other haemoglobinopathies v2.3 Achchuthan Shanmugasundram Panel version 2.2 has been signed off on 2025-04-30
Short QT syndrome v3.15 Achchuthan Shanmugasundram Panel version 3.14 has been signed off on 2025-04-30
Neuronal ceroid lipofuscinosis v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2025-04-30
Iron metabolism disorders - NOT common HFE mutations v3.1 Sarah Leigh Panel version 3.0 has been signed off on 2025-04-30
Iron metabolism disorders - NOT common HFE mutations v3.0 Sarah Leigh promoted panel to version 3.0
Neuronal ceroid lipofuscinosis v3.0 Eleanor Williams promoted panel to version 3.0
Rhabdomyolysis and metabolic muscle disorders v5.5 Achchuthan Shanmugasundram Panel version 5.4 has been signed off on 2025-04-30
Neurological ciliopathies v6.1 Eleanor Williams Panel version 6.0 has been signed off on 2025-04-30
Intellectual disability v9.1 Sarah Leigh Panel version 9.0 has been signed off on 2025-04-30
Neurological ciliopathies v6.0 Eleanor Williams promoted panel to version 6.0
White matter disorders and cerebral calcification - narrow panel v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2025-04-30
Intellectual disability v9.0 Sarah Leigh promoted panel to version 9.0
White matter disorders and cerebral calcification - narrow panel v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Nephrocalcinosis or nephrolithiasis v5.1 Eleanor Williams Panel version 5.0 has been signed off on 2025-04-30
Nephrocalcinosis or nephrolithiasis v5.0 Eleanor Williams promoted panel to version 5.0
Inherited pancreatic cancer v3.1 Sarah Leigh Panel version 3.0 has been signed off on 2025-04-30
Vascular skin disorders v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2025-04-30
Inherited pancreatic cancer v3.0 Sarah Leigh promoted panel to version 3.0
Vascular skin disorders v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Mosaic skin disorders - deep sequencing v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2025-04-30
Mosaic skin disorders - deep sequencing v3.0 Eleanor Williams promoted panel to version 3.0
Ichthyosis and erythrokeratoderma v4.1 Sarah Leigh Panel version 4.0 has been signed off on 2025-04-30
Thoracic aortic aneurysm or dissection (GMS) v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2025-04-30
Ichthyosis and erythrokeratoderma v4.0 Sarah Leigh promoted panel to version 4.0
Monogenic hearing loss v5.1 Eleanor Williams Panel version 5.0 has been signed off on 2025-04-30
Thoracic aortic aneurysm or dissection (GMS) v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Monogenic hearing loss v5.0 Eleanor Williams promoted panel to version 5.0
Hypophosphataemia or rickets v4.1 Sarah Leigh Panel version 4.0 has been signed off on 2025-04-30
Hypophosphataemia or rickets v4.0 Sarah Leigh promoted panel to version 4.0
Skeletal dysplasia v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2025-04-30
Skeletal dysplasia v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Monogenic diabetes v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2025-04-30
Monogenic diabetes v3.0 Eleanor Williams promoted panel to version 3.0
Hypogonadotropic hypogonadism (GMS) v4.1 Sarah Leigh Panel version 4.0 has been signed off on 2025-04-30
Hypogonadotropic hypogonadism (GMS) v4.0 Sarah Leigh promoted panel to version 4.0
Clefting v6.6 Arina Puzriakova Panel version 6.5 has been signed off on 2025-04-30
Skeletal ciliopathies v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2025-04-30
Mitochondrial disorders v9.1 Eleanor Williams Panel version 9.0 has been signed off on 2025-04-30
Catecholaminergic polymorphic VT v5.2 Arina Puzriakova Panel version 5.1 has been signed off on 2025-04-30
Skeletal ciliopathies v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Hypertrophic cardiomyopathy v5.1 Sarah Leigh Panel version 5.0 has been signed off on 2025-04-30
Mitochondrial disorders v9.0 Eleanor Williams promoted panel to version 9.0
Brugada syndrome and cardiac sodium channel disease v3.13 Arina Puzriakova Panel version 3.12 has been signed off on 2025-04-30
Hypertrophic cardiomyopathy v5.0 Sarah Leigh promoted panel to version 5.0
Severe microcephaly v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2025-04-30
Atypical haemolytic uraemic syndrome v3.7 Arina Puzriakova Panel version 3.6 has been signed off on 2025-04-30
Severe microcephaly v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Mitochondrial disorder with complex V deficiency v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2025-04-30
Hereditary neuropathy or pain disorder v7.1 Sarah Leigh Panel version 7.0 has been signed off on 2025-04-30
Mitochondrial disorder with complex V deficiency v3.0 Eleanor Williams promoted panel to version 3.0
Hereditary neuropathy or pain disorder v7.0 Sarah Leigh promoted panel to version 7.0
Arrhythmogenic right ventricular cardiomyopathy v3.14 Arina Puzriakova Panel version 3.13 has been signed off on 2025-04-30
Severe early-onset obesity v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2025-04-30
Mitochondrial disorder with complex IV deficiency v4.1 Eleanor Williams Panel version 4.0 has been signed off on 2025-04-30
Severe early-onset obesity v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Mitochondrial disorder with complex IV deficiency v4.0 Eleanor Williams promoted panel to version 4.0
Congenital muscular dystrophy v6.1 Arina Puzriakova Panel version 6.0 has been signed off on 2025-04-30
Hereditary ataxia with onset in adulthood v8.1 Sarah Leigh Panel version 8.0 has been signed off on 2025-04-30
Congenital muscular dystrophy v6.0 Arina Puzriakova promoted panel to version 6.0
Hereditary ataxia with onset in adulthood v8.0 Sarah Leigh promoted panel to version 8.0
Segmental overgrowth disorders - Deep sequencing v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2025-04-30
Segmental overgrowth disorders - Deep sequencing v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.1 Eleanor Williams Panel version 5.0 has been signed off on 2025-04-30
Congenital hypothyroidism v3.1 Arina Puzriakova Panel version 3.0 has been signed off on 2025-04-30
Congenital hypothyroidism v3.0 Arina Puzriakova promoted panel to version 3.0
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.0 Eleanor Williams promoted panel to version 5.0
Fetal anomalies v6.1 Sarah Leigh Panel version 6.0 has been signed off on 2025-04-30
Congenital fibrosis of the extraocular muscles v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2025-04-30
Congenital fibrosis of the extraocular muscles v2.0 Arina Puzriakova promoted panel to version 2.0
Fetal anomalies v6.0 Sarah Leigh promoted panel to version 6.0
Retinal disorders v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2025-04-30
Congenital disorders of glycosylation v7.1 Arina Puzriakova Panel version 7.0 has been signed off on 2025-04-30
Retinal disorders v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Congenital disorders of glycosylation v7.0 Arina Puzriakova promoted panel to version 7.0
Congenital adrenal hypoplasia v4.1 Arina Puzriakova Panel version 4.0 has been signed off on 2025-04-30
Congenital adrenal hypoplasia v4.0 Arina Puzriakova promoted panel to version 4.0
Respiratory ciliopathies including non-CF bronchiectasis v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2025-04-30
Limb disorders v7.1 Eleanor Williams Panel version 7.0 has been signed off on 2025-04-30
Respiratory ciliopathies including non-CF bronchiectasis v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Cleidocranial Dysplasia v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2025-04-30
Cleidocranial Dysplasia v2.0 Arina Puzriakova promoted panel to version 2.0
Familial hypoparathyroidism v3.1 Sarah Leigh Panel version 3.0 has been signed off on 2025-04-30
Limb disorders v7.0 Eleanor Williams promoted panel to version 7.0
Familial hypoparathyroidism v3.0 Sarah Leigh promoted panel to version 3.0
Childhood solid tumours v5.1 Arina Puzriakova Panel version 5.0 has been signed off on 2025-04-30
Childhood solid tumours v5.0 Arina Puzriakova promoted panel to version 5.0
Renal tubulopathies v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2025-04-30
Childhood onset hereditary spastic paraplegia v8.1 Arina Puzriakova Panel version 8.0 has been signed off on 2025-04-30
Childhood onset hereditary spastic paraplegia v8.0 Arina Puzriakova promoted panel to version 8.0
Renal tubulopathies v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Ehlers Danlos syndrome with a likely monogenic cause v4.1 Sarah Leigh Panel version 4.0 has been signed off on 2025-04-30
Ehlers Danlos syndrome with a likely monogenic cause v4.0 Sarah Leigh promoted panel to version 4.0
Childhood onset dystonia, chorea or related movement disorder v7.1 Arina Puzriakova Panel version 7.0 has been signed off on 2025-04-30
Childhood onset dystonia, chorea or related movement disorder v7.0 Arina Puzriakova promoted panel to version 7.0
Renal ciliopathies v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2025-04-30
Renal ciliopathies v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Cerebral vascular malformations v4.1 Arina Puzriakova Panel version 4.0 has been signed off on 2025-04-30
Ectodermal dysplasia v4.1 Sarah Leigh Panel version 4.0 has been signed off on 2025-04-30
Cerebral vascular malformations v4.0 Arina Puzriakova promoted panel to version 4.0
Likely inborn error of metabolism v8.1 Eleanor Williams Panel version 8.0 has been signed off on 2025-04-30
Ectodermal dysplasia v4.0 Sarah Leigh promoted panel to version 4.0
Bleeding and platelet disorders v4.1 Arina Puzriakova Panel version 4.0 has been signed off on 2025-04-30
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2025-04-30
Bleeding and platelet disorders v4.0 Arina Puzriakova promoted panel to version 4.0
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Early onset or syndromic epilepsy v8.1 Sarah Leigh Panel version 8.0 has been signed off on 2025-04-30
Bilateral congenital or childhood onset cataracts v7.1 Arina Puzriakova Panel version 7.0 has been signed off on 2025-04-30
Bilateral congenital or childhood onset cataracts v7.0 Arina Puzriakova promoted panel to version 7.0
Likely inborn error of metabolism v8.0 Eleanor Williams promoted panel to version 8.0
Early onset or syndromic epilepsy v8.0 Sarah Leigh promoted panel to version 8.0
Ataxia and cerebellar anomalies - narrow panel v8.1 Arina Puzriakova Panel version 8.0 has been signed off on 2025-04-30
Rare genetic inflammatory skin disorders v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2025-04-30
Ataxia and cerebellar anomalies - narrow panel v8.0 Arina Puzriakova promoted panel to version 8.0
Rare genetic inflammatory skin disorders v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Arthrogryposis v9.1 Arina Puzriakova Panel version 9.0 has been signed off on 2025-04-30
Arthrogryposis v9.0 Arina Puzriakova promoted panel to version 9.0
Dilated and arrhythmogenic cardiomyopathy v3.1 Sarah Leigh Panel version 3.0 has been signed off on 2025-04-30
Pulmonary arterial hypertension v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2025-04-30
Laterality disorders and isomerism v4.1 Eleanor Williams Panel version 4.0 has been signed off on 2025-04-30
Dilated and arrhythmogenic cardiomyopathy v3.0 Sarah Leigh promoted panel to version 3.0
Pulmonary arterial hypertension v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Amelogenesis imperfecta v4.1 Arina Puzriakova Panel version 4.0 has been signed off on 2025-04-30
Laterality disorders and isomerism v4.0 Eleanor Williams promoted panel to version 4.0
Amelogenesis imperfecta v4.0 Arina Puzriakova promoted panel to version 4.0
Albinism or congenital nystagmus v4.1 Arina Puzriakova Panel version 4.0 has been signed off on 2025-04-30
Albinism or congenital nystagmus v4.0 Arina Puzriakova promoted panel to version 4.0
DDG2P v6.1 Sarah Leigh Panel version 6.0 has been signed off on 2025-04-30
Proteinuric renal disease v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2025-04-30
Proteinuric renal disease v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Adult onset neurodegenerative disorder v8.1 Arina Puzriakova Panel version 8.0 has been signed off on 2025-04-30
DDG2P v6.0 Sarah Leigh promoted panel to version 6.0
Adult onset neurodegenerative disorder v8.0 Arina Puzriakova promoted panel to version 8.0
Adult onset leukodystrophy v6.1 Arina Puzriakova Panel version 6.0 has been signed off on 2025-04-30
Adult onset leukodystrophy v6.0 Arina Puzriakova promoted panel to version 6.0
Cytopenia - NOT Fanconi anaemia v4.1 Sarah Leigh Panel version 4.0 has been signed off on 2025-04-30
Adult onset hereditary spastic paraplegia v6.1 Arina Puzriakova Panel version 6.0 has been signed off on 2025-04-30
Adult onset hereditary spastic paraplegia v6.0 Arina Puzriakova promoted panel to version 6.0
Cytopenia - NOT Fanconi anaemia v4.0 Sarah Leigh promoted panel to version 4.0
Primary lymphoedema v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2025-04-30
Primary lymphoedema v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Cystic kidney disease v8.1 Sarah Leigh Panel version 8.0 has been signed off on 2025-04-30
Adult onset dystonia, chorea or related movement disorder v5.1 Arina Puzriakova Panel version 5.0 has been signed off on 2025-04-30
Cystic kidney disease v8.0 Sarah Leigh promoted panel to version 8.0
Adult onset dystonia, chorea or related movement disorder v5.0 Arina Puzriakova promoted panel to version 5.0
Acute rhabdomyolysis v2.1 Arina Puzriakova Panel version 2.0 has been signed off on 2025-04-30
Primary immunodeficiency or monogenic inflammatory bowel disease v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2025-04-30
Acute rhabdomyolysis v2.0 Arina Puzriakova promoted panel to version 2.0
Primary immunodeficiency or monogenic inflammatory bowel disease v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Corneal dystrophy v4.1 Sarah Leigh Panel version 4.0 has been signed off on 2025-04-30
Corneal dystrophy v4.0 Sarah Leigh promoted panel to version 4.0
Congenital myopathy v6.1 Sarah Leigh Panel version 6.0 has been signed off on 2025-04-30
Possible mitochondrial disorder - nuclear genes v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2025-04-30
Possible mitochondrial disorder - nuclear genes v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Congenital myopathy v6.0 Sarah Leigh promoted panel to version 6.0
Pituitary hormone deficiency v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2025-04-30
Pituitary hormone deficiency v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Congenital myaesthenic syndrome v5.1 Sarah Leigh Panel version 5.0 has been signed off on 2025-04-30
Pigmentary skin disorders v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2025-04-30
Congenital myaesthenic syndrome v5.0 Sarah Leigh promoted panel to version 5.0
Pigmentary skin disorders v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
PTEN Hamartoma Tumour Syndrome v1.2 Achchuthan Shanmugasundram Panel name changed from PTEN Hamartoma Tumor Syndrome to PTEN Hamartoma Tumour Syndrome
List of related panels changed from R213 to R213; PTEN Hamartoma Tumor Syndrome
Sickle cell, thalassaemia and other haemoglobinopathies v2.2 Achchuthan Shanmugasundram Panel name changed from Thalassaemia and other haemoglobinopathies to Sickle cell, thalassaemia and other haemoglobinopathies
List of related panels changed from R93 to R93; Thalassaemia and other haemoglobinopathies
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v2.2 Achchuthan Shanmugasundram Panel name changed from Haemoglobinopathy trait or carrier testing to Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing
List of related panels changed from R361 to R361; Haemoglobinopathy trait or carrier testing
Intellectual disability v8.243 PRMT9 Shahryar Alavi reviewed gene: PRMT9: Rating: AMBER; Mode of pathogenicity: Other; Publications: PMID: 38561334; Phenotypes: intellectual disability, failure to thrive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Thrombocythaemia v1.5 SH2B3 Terri McVeigh reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1182/blood-2024-210339; Phenotypes: thrombocytosis, myeloproliferative disease, ALL; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital myopathy v5.16 ZC4H2 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: ZC4H2.
Congenital myopathy v5.16 UNC45B Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: UNC45B.
Congenital myopathy v5.16 TRDN Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: TRDN.
Congenital myopathy v5.16 SPTBN4 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: SPTBN4.
Congenital myopathy v5.16 MLIP Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: MLIP.
Congenital myopathy v5.16 LETM1 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: LETM1.
Congenital myopathy v5.16 KY Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: KY.
Congenital myopathy v5.16 GBE1 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: GBE1.
Congenital myopathy v5.16 DNAJB4 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: DNAJB4.
Congenital myopathy v5.16 COL25A1 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: COL25A1.
Congenital myopathy v5.16 COL13A1 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: COL13A1.
Congenital myopathy v5.16 ASCC1 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: ASCC1.
Congenital muscular dystrophy v5.3 POGLUT1 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: POGLUT1.
Congenital muscular dystrophy v5.3 GOSR2 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: GOSR2.
Congenital muscular dystrophy v5.3 GOLGA2 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: GOLGA2.
Congenital muscular dystrophy v5.3 EMD Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: EMD.
Congenital muscular dystrophy v5.3 DTNA Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: DTNA.
Congenital muscular dystrophy v5.3 DPM3 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: DPM3.
Congenital muscular dystrophy v5.3 BET1 Achchuthan Shanmugasundram Tag currently-not-available-via-GLH-non-WGS-testing was removed from gene: BET1.
Skeletal dysplasia v7.42 NEPRO Achchuthan Shanmugasundram commented on gene: NEPRO: The 'new-gene-name' tag has been added to this gene as the official HGNC gene symbol for NEPRO is RMP64.
Skeletal dysplasia v7.42 NEPRO Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: NEPRO.
Intellectual disability v8.243 GAS8 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: GAS8.
DDG2P v5.48 GAS8 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: GAS8.
DDG2P v5.48 GAS8 Achchuthan Shanmugasundram commented on gene: GAS8: The 'new-gene-name' tag has been added as the official HGNC gene symbol for GAS8 is DRC4.
Fetal anomalies v5.98 GAS8 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: GAS8.
Fetal anomalies v5.98 GAS8 Achchuthan Shanmugasundram commented on gene: GAS8
Respiratory ciliopathies including non-CF bronchiectasis v3.37 GAS8 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: GAS8.
Respiratory ciliopathies including non-CF bronchiectasis v3.37 GAS8 Achchuthan Shanmugasundram commented on gene: GAS8
Laterality disorders and isomerism v3.22 GAS8 Achchuthan Shanmugasundram commented on gene: GAS8
Laterality disorders and isomerism v3.22 GAS8 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: GAS8.
Intellectual disability v8.243 CCDC65 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: CCDC65.
Intellectual disability v8.243 CCDC65 Achchuthan Shanmugasundram commented on gene: CCDC65
DDG2P v5.48 CCDC65 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: CCDC65.
DDG2P v5.48 CCDC65 Achchuthan Shanmugasundram commented on gene: CCDC65: The 'new-gene-name' tag has been added as the approved HGNC gene symbol for CCDC65 is DRC2.
Fetal anomalies v5.98 CCDC65 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: CCDC65.
Fetal anomalies v5.98 CCDC65 Achchuthan Shanmugasundram commented on gene: CCDC65
Laterality disorders and isomerism v3.22 CCDC65 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: CCDC65.
Laterality disorders and isomerism v3.22 CCDC65 Achchuthan Shanmugasundram commented on gene: CCDC65
Respiratory ciliopathies including non-CF bronchiectasis v3.37 CCDC65 Achchuthan Shanmugasundram commented on gene: CCDC65
Respiratory ciliopathies including non-CF bronchiectasis v3.37 CCDC65 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: CCDC65.
Fetal anomalies v5.98 ZSCAN10 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ZSCAN10.
DDG2P v5.48 ZBTB47 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ZBTB47.
DDG2P v5.48 PPFIA3 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: PPFIA3.
DDG2P v5.48 PPFIA3 Achchuthan Shanmugasundram edited their review of gene: PPFIA3: Changed phenotypes to: PPFIA3-related neurodevelopmental disorder, Paul-Chao neurodevelopmental syndrome, OMIM:621122
Fetal anomalies v5.98 DISP1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: DISP1.
Holoprosencephaly - NOT chromosomal v5.3 DISP1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: DISP1.
Fetal anomalies v5.98 DISP1 Achchuthan Shanmugasundram Phenotypes for gene: DISP1 were changed from Holoprosencephaly 10, OMIM:62114 to Holoprosencephaly 10, OMIM:621143
Fetal anomalies v5.97 DISP1 Achchuthan Shanmugasundram Tag watchlist was removed from gene: DISP1.
Fetal anomalies v5.97 DISP1 Achchuthan Shanmugasundram Phenotypes for gene: DISP1 were changed from Holoprosencephaly to Holoprosencephaly 10, OMIM:62114
Holoprosencephaly - NOT chromosomal v5.3 DISP1 Achchuthan Shanmugasundram Phenotypes for gene: DISP1 were changed from holoprosencephaly MONDO:0016296 to Holoprosencephaly 10, OMIM:621143
Intellectual disability v8.243 EPB41L3 Julia Baptista gene: EPB41L3 was added
gene: EPB41L3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EPB41L3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPB41L3 were set to 39292993
Phenotypes for gene: EPB41L3 were set to developmental delay; intellectual disability; seizures; hypotonia; neuroregression
Review for gene: EPB41L3 was set to GREEN
Added comment: Six individuals from five unrelated families with global developmental delay, intellectual disability, seizures, hypotonia, neuroregression and delayed myelination. Exome sequencing identified biallelic variants in EPB41L3 in all affected individuals: two nonsense [c.466C>T, p.(R156*); c.2776C>T, p.(R926*)] and three frameshift [c.666delT, p.(F222Lfs*46); c.2289dupC, p.(V764Rfs*19); c.948_949delTG, p.(A317Kfs*33)].
Sources: Literature
Intellectual disability v8.243 EEF1D Julia Baptista gene: EEF1D was added
gene: EEF1D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EEF1D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EEF1D were set to 36576126; 30787422; 38083972; 28097321
Phenotypes for gene: EEF1D were set to Neurodevelopmental disorder; OMIM#621150
Review for gene: EEF1D was set to GREEN
Added comment: Biallelic variants described in at least 5 families from different areas (Syria, Turkey, Oman and China).
Sources: Literature
Intellectual disability v8.243 FBXO22 Julia Baptista gene: FBXO22 was added
gene: FBXO22 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXO22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXO22 were set to 40215970
Phenotypes for gene: FBXO22 were set to neurodevelopmental delay; malformations; OMIM# 621184
Review for gene: FBXO22 was set to GREEN
Added comment: 15 affected children (nine females and six males) and one fetus (16 cases in total) presenting a common core symptomatology of early-onset growth restriction, neurodevelopmental delay, craniofacial abnormalities, and additional poly-malformations (cardiovascular, gastrointestinal, urinal, and endocrinal) (Figure 1A). All individuals belonged to 14 families from four countries of the Greater Middle East region (UAE, KSA, Oman, and Lebanon), of which 12 were identified as consanguineous. Of the 16 cases, three passed away (F7-II:1, F9-II:1, and F13-II:4), and one was a second-trimester termination of pregnancy (TOP) of unknown sex.
Sources: Literature
Fetal anomalies v5.96 C1orf127 Julia Baptista gene: C1orf127 was added
gene: C1orf127 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: C1orf127 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf127 were set to 39753129
Phenotypes for gene: C1orf127 were set to Heterotaxy
Review for gene: C1orf127 was set to GREEN
Added comment: OMIM entry now available for this gene and condition.
The HGNC approved gene name is CIROZ

Sixteen individuals from 10 independently ascertained families with Left-right anomalies with or without Congenital Heart Defects, consistent with Heterotaxy. Family 1 is of European ancestry, and families 9 and 10 are from Central America, while all remaining families were of Middle Eastern background and known to be consanguineous.

Of these 16 affected individuals, three were affected fetuses subjected to termination of pregnancy, and two died in the first year of life due to complex cardiac phenotypes.
Sources: Literature
Laterality disorders and isomerism v3.22 C1orf127 Julia Baptista gene: C1orf127 was added
gene: C1orf127 was added to Laterality disorders and isomerism. Sources: Literature
Mode of inheritance for gene: C1orf127 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf127 were set to 39753129
Phenotypes for gene: C1orf127 were set to Heterotaxy
Review for gene: C1orf127 was set to GREEN
Added comment: OMIM entry now available for this gene and condition.
The HGNC approved gene name is CIROZ

Sixteen individuals from 10 independently ascertained families with Left-right anomalies with or without Congenital Heart Defects, consistent with Heterotaxy. Family 1 is of European ancestry, and families 9 and 10 are from Central America, while all remaining families were of Middle Eastern background and known to be consanguineous.

Of these 16 affected individuals, three were affected fetuses subjected to termination of pregnancy, and two died in the first year of life due to complex cardiac phenotypes.
Sources: Literature
Retinal disorders v7.26 THRB Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: THRB.
Tag Q2_25_ NHS_review tag was added to gene: THRB.
Retinal disorders v7.26 THRB Achchuthan Shanmugasundram Classified gene: THRB as Amber List (moderate evidence)
Retinal disorders v7.26 THRB Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Romana Izakovicova, a new variant (c.283G>C p.(Gly95Arg)) was reported in five probands from her clinical practice and 100k diagnostic discovery patients. Hence, there is sufficient evidence available now for the promotion of this gene to green rating in the next GMS update.
Retinal disorders v7.26 THRB Achchuthan Shanmugasundram Gene: thrb has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.243 SEL1L Julia Baptista gene: SEL1L was added
gene: SEL1L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SEL1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEL1L were set to 37943610, 37943617
Phenotypes for gene: SEL1L were set to Neurodevelopmental disorder
Review for gene: SEL1L was set to GREEN
Added comment: Biallelic missense variants of SEL1L and HRD1 (or SYVN1) in 6 children from 3 independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia, and/or ataxia (Wang et al 2024). Hypomorphic variants.

A biallelic SEL1L variant (p. Cys141Tyr) in 5 patients from a consanguineous Slovakian family reported by Weis et al 2024.

A gene-disease association is now described in OMIM.
Sources: Literature
Likely inborn error of metabolism v7.27 MAN2B2 Julia Baptista reviewed gene: MAN2B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38622837, 31775018, 35637269; Phenotypes: congenital disorders of glycosylation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v6.11 MAN2B2 Julia Baptista reviewed gene: MAN2B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38622837, 31775018, 35637269; Phenotypes: congenital disorder of glycosylation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v7.25 THRB Achchuthan Shanmugasundram edited their review of gene: THRB: Changed rating: GREEN
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.45 SNUPN Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the promotion of this gene to green rating in the next nGMS update.; to: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.45 SNUPN Achchuthan Shanmugasundram Classified gene: SNUPN as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.45 SNUPN Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the promotion of this gene to green rating in the next nGMS update.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.45 SNUPN Achchuthan Shanmugasundram Gene: snupn has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.44 SNUPN Achchuthan Shanmugasundram Phenotypes for gene: SNUPN were changed from muscular dystrophy to Muscular dystrophy, limb-girdle, autosomal recessive 29, OMIM:620793
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.43 SNUPN Achchuthan Shanmugasundram Publications for gene: SNUPN were set to 38413582
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.42 SNUPN Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SNUPN.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.42 SNUPN Achchuthan Shanmugasundram reviewed gene: SNUPN: Rating: GREEN; Mode of pathogenicity: None; Publications: 38366623, 38413582; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 29, OMIM:620793; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v7.23 NPTX1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Jenna Ridley, there are eight unrelated families identified with four different heterozygous missense variants in NPTX1 gene. Seven families were reported with late-onset ataxia, whereas it is early-onset in the six-year-old girl reported in PMID:35560436. There is also functional evidence available for the two variants reported in PMID:34788392.

This gene has been associated with relevant phenotype in OMIM (MIM #620158).

Hence, this gene should be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Jenna Ridley, there are eight unrelated families identified with four different heterozygous missense variants in NPTX1 gene. Seven families were reported with late-onset ataxia, whereas it is early-onset in the six-year-old girl reported in PMID:35560436. There is also functional evidence available for the two variants reported in PMID:34788392.

This gene has been associated with relevant phenotype in OMIM (MIM #620158).

Hence, this gene should be promoted to green rating in the next GMS update.
Hereditary ataxia with onset in adulthood v7.23 NPTX1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Jenna Ridley, there are eight unrelated families identified with four different missense heterozygous NPTX1 variants. Seven families were reported with late-onset ataxia, whereas it is early onset in the six-year-old girl reported in PMID:35560436. There is also functional evidence available.

This gene has been associated with relevant phenotype in OMIM (MIM #620158).

Hence, this gene should be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Jenna Ridley, there are eight unrelated families identified with four different heterozygous missense variants in NPTX1 gene. Seven families were reported with late-onset ataxia, whereas it is early-onset in the six-year-old girl reported in PMID:35560436. There is also functional evidence available for the two variants reported in PMID:34788392.

This gene has been associated with relevant phenotype in OMIM (MIM #620158).

Hence, this gene should be promoted to green rating in the next GMS update.
Hereditary ataxia with onset in adulthood v7.23 NPTX1 Achchuthan Shanmugasundram Classified gene: NPTX1 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v7.23 NPTX1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Jenna Ridley, there are eight unrelated families identified with four different missense heterozygous NPTX1 variants. Seven families were reported with late-onset ataxia, whereas it is early onset in the six-year-old girl reported in PMID:35560436. There is also functional evidence available.

This gene has been associated with relevant phenotype in OMIM (MIM #620158).

Hence, this gene should be promoted to green rating in the next GMS update.
Hereditary ataxia with onset in adulthood v7.23 NPTX1 Achchuthan Shanmugasundram Gene: nptx1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v7.22 NPTX1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: NPTX1.
Tag Q2_25_ NHS_review tag was added to gene: NPTX1.
Hereditary ataxia with onset in adulthood v7.22 NPTX1 Achchuthan Shanmugasundram edited their review of gene: NPTX1: Changed publications to: 34788392, 35285082, 35288776, 35560436
Hereditary ataxia with onset in adulthood v7.22 NPTX1 Achchuthan Shanmugasundram reviewed gene: NPTX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34788392, 35285082, 35288776, PMID:35560436; Phenotypes: Spinocerebellar ataxia 50, OMIM:620158; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia with onset in adulthood v7.22 FAT2 Achchuthan Shanmugasundram Classified gene: FAT2 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v7.22 FAT2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Jenna Ridley, there are four unrelated cases/ families identified with four different heterozygous missense variants in FAT2 gene and reported with late-onset spinocerebellar ataxia. There is some functional work available.

This gene has been associated with relevant phenotype in OMIM (MIM #617769).

This gene should therefore be promoted to green rating in the next GMS update.
Hereditary ataxia with onset in adulthood v7.22 FAT2 Achchuthan Shanmugasundram Gene: fat2 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v7.21 FAT2 Achchuthan Shanmugasundram Publications for gene: FAT2 were set to 29053796; 36339299; 33884300
Hereditary ataxia with onset in adulthood v7.20 FAT2 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: FAT2.
Tag Q2_25_ NHS_review tag was added to gene: FAT2.
Hereditary ataxia with onset in adulthood v7.20 FAT2 Achchuthan Shanmugasundram reviewed gene: FAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29053796, 33884300, 36339299; Phenotypes: Spinocerebellar ataxia 45, OMIM:617769; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral vascular malformations v3.40 EVL Achchuthan Shanmugasundram Classified gene: EVL as Red List (low evidence)
Cerebral vascular malformations v3.40 EVL Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexandra Njegic and reported in PMID:34125151, there is one patient with Moyamoya disease identified with compound heterozygous variants in EVL gene. There are no other cases or functional work available.

This gene has not yet been reported with relevant phenotypes either in OMIM or in Gene2Phenotype.

Hence, this gene should be rated red with current evidence.
Cerebral vascular malformations v3.40 EVL Achchuthan Shanmugasundram Gene: evl has been classified as Red List (Low Evidence).
Cerebral vascular malformations v3.39 EVL Achchuthan Shanmugasundram Phenotypes for gene: EVL were changed from Moyamoya Disease to Moyamoya disease, MONDO:0016820
Cerebral vascular malformations v3.38 EVL Achchuthan Shanmugasundram reviewed gene: EVL: Rating: RED; Mode of pathogenicity: None; Publications: 34125151; Phenotypes: Moyamoya disease, MONDO:0016820; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.42 ACTN2 Achchuthan Shanmugasundram Publications for gene: ACTN2 were set to 30900782; 34170073; 34386585; 34471957; 36116040
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.41 ACTN2 Achchuthan Shanmugasundram Tag Q2_25_ MOI tag was added to gene: ACTN2.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.41 ACTN2 Achchuthan Shanmugasundram edited their review of gene: ACTN2: Changed publications to: 30900782, 34170073, 34386585, 34471957, 36116040, 3831179; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.41 ACTN2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Cassandra Smith, PMID:3831179 reported a different biallelic variant (p.Arg506Gly) in seven patients from five families of Palestinia decent, all presenting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. This variant is suggested to be a possible founder variant, which was confirmed through haplotype analysis in two families.

The MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' as there is sufficient evidence available for the association of biallelic variants with the phenotype.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.41 ACTN2 Achchuthan Shanmugasundram Mode of inheritance for gene: ACTN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral vascular malformations v3.38 KEL Achchuthan Shanmugasundram Classified gene: KEL as Amber List (moderate evidence)
Cerebral vascular malformations v3.38 KEL Achchuthan Shanmugasundram Gene: kel has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v3.37 KEL Achchuthan Shanmugasundram Phenotypes for gene: KEL were changed from Vein of Galen Malformation to vein of Galen aneurysm, MONDO:0015196
Cerebral vascular malformations v3.36 KEL Achchuthan Shanmugasundram reviewed gene: KEL: Rating: AMBER; Mode of pathogenicity: None; Publications: 30578106, 37978175; Phenotypes: vein of Galen aneurysm, MONDO:0015196; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary neuropathy or pain disorder v6.168 HMBS Sarah Leigh Tag Q2_25_expert_review tag was added to gene: HMBS.
Non-acute porphyrias v1.26 HMBS Sarah Leigh Tag Q2_25_ demote_red tag was added to gene: HMBS.
Tag Q2_25_ MOI tag was added to gene: HMBS.
Tag Q2_25_expert_review tag was added to gene: HMBS.
Non-acute porphyrias v1.26 HMBS Sarah Leigh reviewed gene: HMBS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v7.27 HMBS Sarah Leigh Tag Q2_25_ MOI tag was added to gene: HMBS.
Tag Q2_25_expert_review tag was added to gene: HMBS.
Likely inborn error of metabolism v7.27 HMBS Sarah Leigh reviewed gene: HMBS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Likely inborn error of metabolism v7.27 HMBS Sarah Leigh Phenotypes for gene: HMBS were changed from Porphyria, acute intermittent, nonerythroid variant, 176000; Acute intermittent porphyria (Acute neuropathic porphyrias); Porphyria, acute intermittent, 176000 to Porphyria, acute intermittent OMIM:176000; acute intermittent porphyria MONDO:0008294; Leukoencephalopathy, porphyria-related OMIM:620711; leukoencephalopathy, porphyria-related, MONDO:0958226; Encephalopathy, porphyria-related, OMIM:620704; encephalopathy, porphyria-related, MONDO:0958224
Likely inborn error of metabolism v7.26 HMBS Sarah Leigh Publications for gene: HMBS were set to 27604308
Cutaneous photosensitivity with a likely genetic cause v3.9 HMBS Sarah Leigh commented on gene: HMBS: Based on review from Sharon Whatley (International Porphyria Network), changed MOI from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Cutaneous photosensitivity with a likely genetic cause v3.9 HMBS Sarah Leigh Deleted their comment
Cutaneous photosensitivity with a likely genetic cause v3.9 HMBS Sarah Leigh Phenotypes for gene: HMBS were changed from Porphyria, acute intermittent, 176000; Acute intermittent porphyria (Acute neuropathic porphyrias); Porphyria, acute intermittent, nonerythroid variant, 176000 to Porphyria, acute intermittent, OMIM:176000; Porphyria, acute intermittent, nonerythroid variant, OMIM:176000; Leukoencephalopathy, porphyria-related OMIM:620711; leukoencephalopathy, porphyria-related, MONDO:0958226; Encephalopathy, porphyria-related, OMIM:620704; encephalopathy, porphyria-related, MONDO:0958224
Cutaneous photosensitivity with a likely genetic cause v3.8 HMBS Sarah Leigh Added comment: Comment on phenotypes: Porphyria, acute intermittent, OMIM:176000;Porphyria, acute intermittent, nonerythroid variant, OMIM:176000;Leukoencephalopathy, porphyria-related OMIM:620711; leukoencephalopathy, porphyria-related, MONDO:0958226; Encephalopathy, porphyria-related, OMIM:620704; encephalopathy, porphyria-related, MONDO:0958224
Cutaneous photosensitivity with a likely genetic cause v3.8 HMBS Sarah Leigh Phenotypes for gene: HMBS were changed from Porphyria, acute intermittent, 176000; Acute intermittent porphyria (Acute neuropathic porphyrias); Porphyria, acute intermittent, nonerythroid variant, 176000 to Porphyria, acute intermittent, 176000; Acute intermittent porphyria (Acute neuropathic porphyrias); Porphyria, acute intermittent, nonerythroid variant, 176000
Cutaneous photosensitivity with a likely genetic cause v3.7 HMBS Sarah Leigh Publications for gene: HMBS were set to
Cutaneous photosensitivity with a likely genetic cause v3.6 HMBS Sarah Leigh Mode of inheritance for gene: HMBS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.168 HMBS Sarah Leigh Tag Q2_25_ MOI tag was added to gene: HMBS.
Hereditary neuropathy or pain disorder v6.168 HMBS Sarah Leigh edited their review of gene: HMBS: Added comment: Based on review from Sharon Whatley (International Porphyria Network), the mode of inheritance of HMBS should be changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal on this panel - Hereditary neuropathy or pain disorder.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v6.10 HMBS Sarah Leigh Mode of inheritance for gene: HMBS was changed from to BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v6.8 HMBS Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: HMBS.
Bilateral congenital or childhood onset cataracts v6.8 HMBS Sarah Leigh reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bilateral congenital or childhood onset cataracts v6.8 HMBS Sarah Leigh Phenotypes for gene: HMBS were changed from 620711; 620704 to Leukoencephalopathy, porphyria-related, OMIM: 620711; Encephalopathy, porphyria-related, OMIM: 620704
Bilateral congenital or childhood onset cataracts v6.7 HMBS Sarah Leigh Classified gene: HMBS as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v6.7 HMBS Sarah Leigh Gene: hmbs has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v7.31 HMBS Sarah Leigh Publications for gene: HMBS were set to 27558376; 34089223
Acute intermittent porphyria v1.3 HMBS Sarah Leigh reviewed gene: HMBS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Acute intermittent porphyria v1.3 HMBS Sarah Leigh Tag Q2_25_ MOI tag was added to gene: HMBS.
Tag Q2_25_expert_review tag was added to gene: HMBS.
Acute intermittent porphyria v1.3 HMBS Sarah Leigh Phenotypes for gene: HMBS were changed from to Porphyria, acute intermittent, nonerythroid variant, OMIM:176000; Porphyria, acute intermittent, OMIM:176000; acute intermittent porphyria, MONDO:0008294; Encephalopathy, porphyria-related, OMIM:620704; encephalopathy, porphyria-related, MONDO:0958224; Leukoencephalopathy, porphyria-related, OMIM: 620711
White matter disorders and cerebral calcification - narrow panel v6.11 HMBS Sarah Leigh Publications for gene: HMBS were set to 27558376; 34089223
Non-acute porphyrias v1.26 HMBS Sarah Leigh Publications for gene: HMBS were set to 27604308; 2511016; 1714233
Non-acute porphyrias v1.25 HMBS Sarah Leigh Phenotypes for gene: HMBS were changed from Porphyria, acute intermittent, nonerythroid variant OMIM:176000; Porphyria, acute intermittent OMIM:176000; acute intermittent porphyria MONDO:0008294 to Porphyria, acute intermittent OMIM:176000; acute intermittent porphyria MONDO:0008294; Leukoencephalopathy, porphyria-related OMIM:620711; leukoencephalopathy, porphyria-related, MONDO:0958226; Encephalopathy, porphyria-related, OMIM:620704; encephalopathy, porphyria-related, MONDO:0958224
Hereditary neuropathy or pain disorder v6.168 HMBS Sarah Leigh Added comment: Comment on publications: Publications suggested by Sharon Whatley (International Porphyria Network): 27539938; 38940544; 35584894; 14262853; 1577472; 15534187; 31153822; 14970743; 34089223; 27558376
Hereditary neuropathy or pain disorder v6.168 HMBS Sarah Leigh Publications for gene: HMBS were set to 27558376; 34089223
Childhood onset hereditary spastic paraplegia v7.14 HMBS Sarah Leigh Phenotypes for gene: HMBS were changed from Leukoencephalopathy, porphyria-related, OMIM:620711; hereditary spastic paraplegia, MONDO:0019064 to Leukoencephalopathy, porphyria-related, OMIM:620711; Encephalopathy, porphyria-related, OMIM:620704
Childhood onset hereditary spastic paraplegia v7.13 HMBS Sarah Leigh Phenotypes for gene: HMBS were changed from Leukoencephalopathy, HP:0002352; hereditary spastic paraplegia, MONDO:0019064 to Leukoencephalopathy, porphyria-related, OMIM:620711; hereditary spastic paraplegia, MONDO:0019064
Childhood onset hereditary spastic paraplegia v7.12 HMBS Sarah Leigh Publications for gene: HMBS were set to 27558376; 34089223
Childhood onset dystonia, chorea or related movement disorder v6.9 HMBS Sarah Leigh Publications for gene: HMBS were set to
Acute intermittent porphyria v1.2 HMBS Sarah Leigh Publications for gene: HMBS were set to
Fetal anomalies v5.96 GPKOW Sarah Leigh reviewed gene: GPKOW: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v5.96 GPKOW Sarah Leigh Phenotypes for gene: GPKOW were changed from male-lethal microcephaly with intrauterine growth restriction to microcephaly with intrauterine growth restriction
Fetal anomalies v5.95 GPKOW Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: GPKOW.
Fetal anomalies v5.95 GPKOW Sarah Leigh Mode of inheritance for gene: GPKOW was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Fetal anomalies v5.94 GPKOW Sarah Leigh Publications for gene: GPKOW were set to 28612833
Familial breast cancer v1.20 BARD1 Terri McVeigh reviewed gene: BARD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33471991; Phenotypes: breast cancer; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
GI tract tumours v1.22 MBD4 Terri McVeigh reviewed gene: MBD4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35460607, PMID: 30049810, PMID: 35381620, PMID: 32421892, PMID: 32239153; Phenotypes: MBD4-Associated Neoplasia Syndrome: Colonic polyposis, colon cancer, uveal melanoma, acute myeloid leukaemia, schwannoma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia v1.342 RAB3A Sarah Leigh Classified gene: RAB3A as Green List (high evidence)
Hereditary ataxia v1.342 RAB3A Sarah Leigh Gene: rab3a has been classified as Green List (High Evidence).
Hereditary ataxia v1.341 RAB3A Sarah Leigh edited their review of gene: RAB3A: Added comment: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood. The authors also present supportive functional studies.; Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v7.30 RAB3A Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: RAB3A.
Tag Q2_25_ NHS_review tag was added to gene: RAB3A.
Ataxia and cerebellar anomalies - narrow panel v7.30 RAB3A Sarah Leigh edited their review of gene: RAB3A: Added comment: Hengel et al (PMID: 40166812) report six heterozygous RAB3A variants which appear to be associated with a condition that includes cerebellar ataxia; pyramidal features; neurodevelopmental delay. Five of the variants were only seen in one family each, while (NM_002866.5) c.247C>T (p.Arg83Trp) was seen in 14 members from nine families. The age of onset of phenotypic features ranged from 3 months to adulthood. The authors also present supportive functional studies.; Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v7.30 RAB3A Sarah Leigh Entity copied from Hereditary ataxia v1.341
Ataxia and cerebellar anomalies - narrow panel v7.30 RAB3A Sarah Leigh gene: RAB3A was added
gene: RAB3A was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber,Research
Mode of inheritance for gene: RAB3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB3A were set to 36928819; 40166812
Phenotypes for gene: RAB3A were set to RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay
Penetrance for gene: RAB3A were set to Complete
Hereditary ataxia v1.341 RAB3A Sarah Leigh Classified gene: RAB3A as Amber List (moderate evidence)
Hereditary ataxia v1.341 RAB3A Sarah Leigh Gene: rab3a has been classified as Amber List (Moderate Evidence).
Hereditary ataxia v1.340 RAB3A Sarah Leigh Added comment: Comment on phenotypes: RAB3A variants have not yet been associated with a phenotype in OMIM
Hereditary ataxia v1.340 RAB3A Sarah Leigh Phenotypes for gene: RAB3A were changed from cerebellar ataxia; pyramidal features; neurodevelopmental delay to RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay
Hereditary ataxia v1.339 RAB3A Sarah Leigh Publications for gene: RAB3A were set to PMID:36928819; 40166812
Adult onset neurodegenerative disorder v7.24 CACNA1A_CAG Sarah Leigh Tag watchlist was removed from STR: CACNA1A_CAG.
Tag Q2_25_ promote_green tag was added to STR: CACNA1A_CAG.
Childhood onset hereditary spastic paraplegia v7.11 CACNA1A_CAG Sarah Leigh reviewed STR: CACNA1A_CAG: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v7.24 CACNA1A_CAG Sarah Leigh Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6, OMIM:183086 to Spinocerebellar ataxia 6, OMIM:183086; spinocerebellar ataxia type 6, MONDO:0008457
Childhood onset hereditary spastic paraplegia v7.11 CACNA1A_CAG Sarah Leigh Publications for STR: CACNA1A_CAG were set to
Adult onset neurodegenerative disorder v7.23 CACNA1A_CAG Sarah Leigh Publications for STR: CACNA1A_CAG were set to
Adult onset neurodegenerative disorder v7.22 CACNA1A_CAG Sarah Leigh changed review comment from: There are numerous reports of CACNA1A_CAG repeat expansions in cases of Spinocerebellar ataxia 6 (OMIM: 183086)(PMID: 18285829;19817876;16595610;8988170). The age of onset of OMIM: 183086 is typically 20-65 years.; to: There are numerous reports of CACNA1A_CAG repeat expansions in cases of Spinocerebellar ataxia 6 (OMIM: 183086)(PMID: 18285829;19817876;16595610;8988170). The age of onset of OMIM: 183086 is typically 20-65 years (PMID: 9311738).
Adult onset neurodegenerative disorder v7.22 CACNA1A_CAG Sarah Leigh reviewed STR: CACNA1A_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v7.29 CACNA1A_CAG Sarah Leigh Tag watchlist was removed from STR: CACNA1A_CAG.
Tag Q2_25_ promote_green tag was added to STR: CACNA1A_CAG.
Ataxia and cerebellar anomalies - narrow panel v7.29 CACNA1A_CAG Sarah Leigh reviewed STR: CACNA1A_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v7.29 CACNA1A_CAG Sarah Leigh Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6, OMIM:183086 to Spinocerebellar ataxia 6, OMIM:183086; spinocerebellar ataxia type 6, MONDO:0008457
Ataxia and cerebellar anomalies - narrow panel v7.28 CACNA1A_CAG Sarah Leigh Publications for STR: CACNA1A_CAG were set to
Early onset dystonia v1.149 ATXN10_ATTCT Sarah Leigh Tag curated_removed was removed from STR: ATXN10_ATTCT.
Thoracic dystrophies v1.21 ATXN10_ATTCT Sarah Leigh Tag curated_removed was removed from STR: ATXN10_ATTCT.
Thoracic dystrophies v1.21 ATXN10_ATTCT Sarah Leigh reviewed STR: ATXN10_ATTCT: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Thoracic dystrophies v1.21 ATXN10_ATTCT Sarah Leigh Classified STR: ATXN10_ATTCT as Red List (low evidence)
Thoracic dystrophies v1.21 ATXN10_ATTCT Sarah Leigh Str: atxn10_attct has been classified as Red List (Low Evidence).
Early onset dystonia v1.149 ATXN10_ATTCT Sarah Leigh Classified STR: ATXN10_ATTCT as Red List (low evidence)
Early onset dystonia v1.149 ATXN10_ATTCT Sarah Leigh Str: atxn10_attct has been classified as Red List (Low Evidence).
Early onset dystonia v1.148 ATXN10_ATTCT Sarah Leigh reviewed STR: ATXN10_ATTCT: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v8.243 ATXN10_ATTCT Sarah Leigh Classified STR: ATXN10_ATTCT as Amber List (moderate evidence)
Intellectual disability v8.243 ATXN10_ATTCT Sarah Leigh Str: atxn10_attct has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.242 ATXN10_ATTCT Sarah Leigh reviewed STR: ATXN10_ATTCT: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v8.242 ATXN10_ATTCT Sarah Leigh Tag curated_removed was removed from STR: ATXN10_ATTCT.
Early onset or syndromic epilepsy v7.90 RNU4-2 Hayley Lees reviewed gene: RNU4-2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v8.242 RNU4-2 Hayley Lees reviewed gene: RNU4-2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v7.10 ATXN10_ATTCT Sarah Leigh Tag Q2_25_ promote_green tag was added to STR: ATXN10_ATTCT.
Adult onset neurodegenerative disorder v7.22 ATXN10_ATTCT Sarah Leigh Tag watchlist was removed from STR: ATXN10_ATTCT.
Tag Q2_25_ promote_green tag was added to STR: ATXN10_ATTCT.
Childhood onset hereditary spastic paraplegia v7.10 ATXN10_ATTCT Sarah Leigh edited their review of STR: ATXN10_ATTCT: Changed rating: GREEN
Childhood onset hereditary spastic paraplegia v7.10 ATXN10_ATTCT Sarah Leigh reviewed STR: ATXN10_ATTCT: Rating: ; Mode of pathogenicity: None; Publications: 17420323, 15505178; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v7.22 ATXN10_ATTCT Sarah Leigh reviewed STR: ATXN10_ATTCT: Rating: GREEN; Mode of pathogenicity: None; Publications: 17420323, 15505178; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v7.22 ATXN10_ATTCT Sarah Leigh Publications for STR: ATXN10_ATTCT were set to 12164725; 35441258; 36199580; 40067487
Ataxia and cerebellar anomalies - narrow panel v7.27 ATXN10_ATTCT Sarah Leigh Tag watchlist was removed from STR: ATXN10_ATTCT.
Tag Q2_25_ promote_green tag was added to STR: ATXN10_ATTCT.
Ataxia and cerebellar anomalies - narrow panel v7.27 ATXN10_ATTCT Sarah Leigh reviewed STR: ATXN10_ATTCT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v7.42 ATXN10_ATTCT Sarah Leigh Classified STR: ATXN10_ATTCT as Red List (low evidence)
Skeletal dysplasia v7.42 ATXN10_ATTCT Sarah Leigh Str: atxn10_attct has been classified as Red List (Low Evidence).
Skeletal dysplasia v7.41 ATXN10_ATTCT Sarah Leigh Tag curated_removed was removed from STR: ATXN10_ATTCT.
Skeletal dysplasia v7.41 ATXN10_ATTCT Sarah Leigh reviewed STR: ATXN10_ATTCT: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v7.41 ATXN10_ATTCT Sarah Leigh Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10, OMIM:603516 to Spinocerebellar ataxia 10, OMIM:603516; spinocerebellar ataxia type 10, MONDO:0011330
Skeletal dysplasia v7.40 ATXN10_ATTCT Sarah Leigh Publications for STR: ATXN10_ATTCT were set to 12164725
Adult onset neurodegenerative disorder v7.21 ATXN10_ATTCT Sarah Leigh Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10, OMIM:603516 to Spinocerebellar ataxia 10, OMIM:603516; spinocerebellar ataxia type 10, MONDO:0011330
Childhood onset hereditary spastic paraplegia v7.10 ATXN10_ATTCT Sarah Leigh Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10, OMIM:603516 to Spinocerebellar ataxia 10, OMIM:603516; spinocerebellar ataxia type 10, MONDO:0011330
Adult onset neurodegenerative disorder v7.20 ATXN10_ATTCT Sarah Leigh Publications for STR: ATXN10_ATTCT were set to
Childhood onset hereditary spastic paraplegia v7.9 ATXN10_ATTCT Sarah Leigh Publications for STR: ATXN10_ATTCT were set to
Ataxia and cerebellar anomalies - narrow panel v7.27 ATXN10_ATTCT Sarah Leigh Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10, OMIM:603516 to Spinocerebellar ataxia 10, OMIM:603516; spinocerebellar ataxia type 10, MONDO:0011330
Ataxia and cerebellar anomalies - narrow panel v7.26 ATXN10_ATTCT Sarah Leigh Publications for STR: ATXN10_ATTCT were set to 12164725
Hypertrophic cardiomyopathy v4.21 ALPK3 Riyaad Aungraheeta reviewed gene: ALPK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 40255155; Phenotypes: Hypertrophic cardiomyopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Cerebral vascular malformations v3.36 NOS3 Achchuthan Shanmugasundram Classified gene: NOS3 as Amber List (moderate evidence)
Cerebral vascular malformations v3.36 NOS3 Achchuthan Shanmugasundram Gene: nos3 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v3.35 NOS3 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: NOS3.
Cerebral vascular malformations v3.35 NOS3 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Alexandra Njegic, there are two unrelated cases and some functional evidence available for the association of biallelic variants with MMA. However, there is only one case with monoallelic NOS3 variant. The pathogenicity of this monoallelic variant was not explored in detail in the publication.

Hence, the gene should be rated amber and the MOI should be set to BIALLELIC.

The 'watchlist' tag has been added to review this gene in light of new evidence.
Cerebral vascular malformations v3.35 NOS3 Achchuthan Shanmugasundram Mode of inheritance for gene: NOS3 was changed from Other to BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v3.34 NOS3 Achchuthan Shanmugasundram Publications for gene: NOS3 were set to 37383439; 36941667
Cerebral vascular malformations v3.33 NOS3 Achchuthan Shanmugasundram Phenotypes for gene: NOS3 were changed from Moyamoya Disease; Moyamoya Angiopathy to Moyamoya disease, MONDO:0016820
Cerebral vascular malformations v3.32 NOS3 Achchuthan Shanmugasundram reviewed gene: NOS3: Rating: AMBER; Mode of pathogenicity: None; Publications: 36941667, 37383439; Phenotypes: Moyamoya disease, MONDO:0016820; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.167 RCC1 Lauren Turton gene: RCC1 was added
gene: RCC1 was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS
Mode of inheritance for gene: RCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Review for gene: RCC1 was set to AMBER
Added comment: Present in medrxiv, https://www.medrxiv.org/content/10.1101/2024.10.04.24314535v1. As not formally published left as amber rating.
24 individuals from 12 families with acute onset axonal neuropathy. Very severe disease in acutely unwell children. Neurological presentation was secondary to infection.
Sources: NHS GMS
Structural eye disease v4.8 ARR3 Sarah Leigh changed review comment from: Six ARR3 variant have been seen in seven unrelated families with Myopia 26, X-linked, female-limited, OMIM:301010. The inheritance of the causative ARR3 variants is X‐linked female limited, in that only the female carriers of the variant display the phenotype - OMIM:301010 (PMID: 35001458;33482870;27829781).; to: Six ARR3 variants have been seen in seven unrelated families with Myopia 26, X-linked, female-limited (OMIM:301010). The inheritance of the causative ARR3 variants is X‐linked female limited, in that only the female carriers of the variant display the phenotype - OMIM:301010 (PMID: 35001458;33482870;27829781).
Cerebral vascular malformations v3.32 CBL Achchuthan Shanmugasundram Phenotypes for gene: CBL were changed from early-onset moyamoya angiopathy; moyamoya disease, MONDO:0016820; Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, OMIM:613563 to cerebral arterial disease, MONDO:0006693; Moyamoya disease, MONDO:0016820; early-onset moyamoya angiopathy; Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, OMIM:613563
Cerebral vascular malformations v3.31 CBL Achchuthan Shanmugasundram Publications for gene: CBL were set to 28343148; 25283271; 28589114
Cerebral vascular malformations v3.30 CBL Achchuthan Shanmugasundram Mode of inheritance for gene: CBL was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral vascular malformations v3.29 CBL Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: CBL.
Tag Q2_25_expert_review tag was added to gene: CBL.
Tag Q2_25_ NHS_review tag was added to gene: CBL.
Cerebral vascular malformations v3.29 CBL Achchuthan Shanmugasundram Classified gene: CBL as Amber List (moderate evidence)
Cerebral vascular malformations v3.29 CBL Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexandra Njegic, there are five patients from three unrelated families reported with three different CBL variants and cerebral arteriopathy in PMID:32637631, and one patient was reported with the previously identified de novo splice variant in CBL gene in PMID:37778001. The patient from PMID:37778001 also had a maternally inherited VUS variant in RNF213 gene. This is also some functional evidence available.

There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update. However, it has been tagged for expert review from the GMS.
Cerebral vascular malformations v3.29 CBL Achchuthan Shanmugasundram Gene: cbl has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v3.28 CBL Achchuthan Shanmugasundram reviewed gene: CBL: Rating: GREEN; Mode of pathogenicity: None; Publications: 32637631, 37778001; Phenotypes: cerebral arterial disease, MONDO:0006693, Moyamoya disease, MONDO:0016820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral vascular malformations v3.28 FOXM1 Achchuthan Shanmugasundram Classified gene: FOXM1 as Amber List (moderate evidence)
Cerebral vascular malformations v3.28 FOXM1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexandra Njegic, PMID:38969938 reported a 60-year-old father and 31-year-old daughter with unilateral Moyamoya Disease and with c.1205 C > A variant in FOXM1 gene (p.(Ala402Glu). There is also functional evidence available for the identified variant from the publication.

This gene should be rated amber with current evidence.
Cerebral vascular malformations v3.28 FOXM1 Achchuthan Shanmugasundram Gene: foxm1 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v3.27 FOXM1 Achchuthan Shanmugasundram Phenotypes for gene: FOXM1 were changed from Moyamoya Disease (Unilateral) to Moyamoya disease, MONDO:0016820
Cerebral vascular malformations v3.26 FOXM1 Achchuthan Shanmugasundram edited their review of gene: FOXM1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cerebral vascular malformations v3.26 FOXM1 Achchuthan Shanmugasundram reviewed gene: FOXM1: Rating: AMBER; Mode of pathogenicity: None; Publications: 38969938; Phenotypes: Moyamoya disease, MONDO:0016820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Renal ciliopathies v3.20 DLG5 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: DLG5.
Tag Q2_25_expert_review tag was added to gene: DLG5.
Tag Q2_25_ NHS_review tag was added to gene: DLG5.
Renal ciliopathies v3.20 DLG5 Sarah Leigh edited their review of gene: DLG5: Added comment: With reference to the review of the published evidence by Tracy Lester (Genetics laboratory, Oxford UK), a change of mode of inheritance is suggested from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal. Four biallelic DLG5 variants have been reported in three unrelated cases (PMID: 30791088, 32631816). Three monoallelic DLG5 variants have been reported (PMID: 32631816, 35361250). The de novo variant c.745C>T(p.Arg249Trp) is present in 9 heterozygotes and 1 homozygote in gnomad v4.1, while the phenotype is mild for the heterozygous carriers of c.4526AG>TT (p.Gln1509Leu)(PMID: 32631816). A further monoallelic DLG5 variant was reported in a case with Müllerian agenesis (PMID: 35361250).; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal ciliopathies v3.20 DLG5 Sarah Leigh Publications for gene: DLG5 were set to 32631816; 30791088; 17765678
Renal ciliopathies v3.19 DLG5 Sarah Leigh Publications for gene: DLG5 were set to 32631816; 17765678
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.40 JAG2 Lauren Turton changed review comment from: This gene is currently green on the R79 congenital muscular dystrophy panel.
PMID: 33861953 initial paper on this gene. 23 patients from 13 unrelated families.
PMID: 39121631 three additional patients who presented with childhood onset limb girdle myopathy.
PMID: 39649397 two additional patients presenting with childhood onset muscle hypotonia predominatly affecting the pelvic girdle and proximal leg muscles.
Sources: NHS GMS; to: This gene is currently green on the R79 congenital muscular dystrophy panel.
PMID: 33861953 initial paper on this gene. 23 patients from 13 unrelated families.
PMID: 39121631 three additional patients who presented with childhood onset limb girdle myopathy.
PMID: 39649397 two additional patients presenting with childhood onset muscle hypotonia predominantly affecting the pelvic girdle and proximal leg muscles.
Sources: NHS GMS
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.40 JAG2 Lauren Turton gene: JAG2 was added
gene: JAG2 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: NHS GMS
Mode of inheritance for gene: JAG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JAG2 were set to 33861953; 39121631; 39649397
Phenotypes for gene: JAG2 were set to Limb-girdle muscular dystrophy-27 (OMIM: 619566)
Review for gene: JAG2 was set to GREEN
gene: JAG2 was marked as current diagnostic
Added comment: This gene is currently green on the R79 congenital muscular dystrophy panel.
PMID: 33861953 initial paper on this gene. 23 patients from 13 unrelated families.
PMID: 39121631 three additional patients who presented with childhood onset limb girdle myopathy.
PMID: 39649397 two additional patients presenting with childhood onset muscle hypotonia predominatly affecting the pelvic girdle and proximal leg muscles.
Sources: NHS GMS
Structural eye disease v4.8 ARR3 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: ARR3.
Structural eye disease v4.8 ARR3 Sarah Leigh Added comment: Comment on mode of inheritance: X‐linked female limited
Structural eye disease v4.8 ARR3 Sarah Leigh Mode of inheritance for gene: ARR3 was changed from Other to Other
Structural eye disease v4.7 ARR3 Sarah Leigh reviewed gene: ARR3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Other
Structural eye disease v4.7 ARR3 Sarah Leigh Publications for gene: ARR3 were set to 35001458
Structural eye disease v4.6 ARR3 Sarah Leigh Phenotypes for gene: ARR3 were changed from to Myopia 26, X-linked, female-limited, OMIM:301010; myopia 26, X-linked, female-limited, MONDO:0049221
Structural eye disease v4.5 ARR3 Sarah Leigh Classified gene: ARR3 as Amber List (moderate evidence)
Structural eye disease v4.5 ARR3 Sarah Leigh Gene: arr3 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v3.22 AL117258.1 Achchuthan Shanmugasundram commented on gene: AL117258.1: The 'new-gene-name' tag has been added as the HGNC approved symbol for this gene is CIROP. This gene was known by the previous symbol LMLN2.
Laterality disorders and isomerism v3.22 AL117258.1 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: AL117258.1.
Tag gene-checked tag was added to gene: AL117258.1.
Primary immunodeficiency or monogenic inflammatory bowel disease v7.27 C2 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: C2.
Tag Q2_25_expert_review tag was added to gene: C2.
Primary immunodeficiency or monogenic inflammatory bowel disease v7.27 C2 Sarah Leigh reviewed gene: C2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: C2 deficiency, OMIM:217000, complement component 2 deficiency, MONDO:0009006; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v7.27 C2 Sarah Leigh Publications for gene: C2 were set to 1577763; 8621452; 11079100; 15643297; 7901282
Likely inborn error of metabolism v7.25 IDH1 Sarah Leigh edited their review of gene: IDH1: Added comment: Numerous reports of IDH1 variants associated with OMIM:614875, OMIM:614569 and OMIM:166000 (PMID: 24049096; 22025298; 22057234; 22057236).; Changed rating: GREEN
Mitochondrial disorders v8.31 IDH1 Sarah Leigh edited their review of gene: IDH1: Added comment: Numerous reports of IDH1 variants associated with OMIM:614875, OMIM:614569 and OMIM:166000 (PMID: 24049096; 22025298; 22057234; 22057236).; Changed rating: GREEN
Likely inborn error of metabolism v7.25 IDH1 Sarah Leigh Tag mosaicism tag was added to gene: IDH1.
Tag Q2_25_ promote_green tag was added to gene: IDH1.
Mitochondrial disorders v8.31 IDH1 Sarah Leigh Tag mosaicism tag was added to gene: IDH1.
Tag Q2_25_ promote_green tag was added to gene: IDH1.
Likely inborn error of metabolism v7.25 IDH1 Sarah Leigh Classified gene: IDH1 as Amber List (moderate evidence)
Likely inborn error of metabolism v7.25 IDH1 Sarah Leigh Added comment: Comment on list classification: Somatic variants relevant to this gene, potentially resulting in mosaicism
Likely inborn error of metabolism v7.25 IDH1 Sarah Leigh Gene: idh1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v8.31 IDH1 Sarah Leigh Classified gene: IDH1 as Amber List (moderate evidence)
Mitochondrial disorders v8.31 IDH1 Sarah Leigh Added comment: Comment on list classification: Somatic variants relevant to this gene, potentially resulting in mosaicism
Mitochondrial disorders v8.31 IDH1 Sarah Leigh Gene: idh1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v7.24 IDH1 Sarah Leigh Publications for gene: IDH1 were set to 33340416
Mitochondrial disorders v8.30 IDH1 Sarah Leigh Publications for gene: IDH1 were set to 24049096 22025298 22057234 22057236; 33340416
Mitochondrial disorders v8.29 IDH1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gain of function variants associated with Maffucci syndrome and Ollier disease (PMID: 22057234)
Mitochondrial disorders v8.29 IDH1 Sarah Leigh Mode of pathogenicity for gene: IDH1 was changed from None to None
Likely inborn error of metabolism v7.23 IDH1 Sarah Leigh Added comment: Comment on mode of inheritance: Somatic variants thought to occur early in development, resulting in mosaicism
Likely inborn error of metabolism v7.23 IDH1 Sarah Leigh Mode of inheritance for gene: IDH1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mitochondrial disorders v8.28 IDH1 Sarah Leigh Added comment: Comment on mode of inheritance: Somatic variants thought to occur early in development, resulting in mosaicism
Mitochondrial disorders v8.28 IDH1 Sarah Leigh Mode of inheritance for gene: IDH1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Likely inborn error of metabolism v7.22 IDH1 Sarah Leigh Phenotypes for gene: IDH1 were changed from Failure to thrive; Psychomotor delay; Feeding difficulties; Increased D-2-Hydroxyglutaric acid in urine to Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria OMIM:614875; metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, MONDO:0013941; Maffucci syndrome, OMIM:614569; Maffucci syndrome, MONDO:0013808; Ollier disease/ Dyschondroplasia, OMIM:166000; Ollier disease, MONDO:0008145
Mitochondrial disorders v8.27 IDH1 Sarah Leigh Phenotypes for gene: IDH1 were changed from Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria to Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria OMIM:614875; metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, MONDO:0013941; Maffucci syndrome, OMIM:614569; Maffucci syndrome, MONDO:0013808; Ollier disease/ Dyschondroplasia, OMIM:166000; Ollier disease, MONDO:0008145
Skeletal dysplasia v7.39 IDH1 Sarah Leigh Phenotypes for gene: IDH1 were changed from Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria 614875; Maffucci syndrome 614569; Ollier disease/ Dyschondroplasia 166000 to Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria OMIM:614875; metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, MONDO:0013941; Maffucci syndrome, OMIM:614569; Maffucci syndrome, MONDO:0013808; Ollier disease/ Dyschondroplasia, OMIM:166000; Ollier disease, MONDO:0008145
Mitochondrial disorders v8.26 IDH1 Sarah Leigh Publications for gene: IDH1 were set to 33340416
Mitochondrial disorders v8.25 SLC13A5 Sarah Leigh Classified gene: SLC13A5 as Red List (low evidence)
Mitochondrial disorders v8.25 SLC13A5 Sarah Leigh Gene: slc13a5 has been classified as Red List (Low Evidence).
Mitochondrial disorders v8.24 SLC13A5 Sarah Leigh reviewed gene: SLC13A5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
White matter disorders and cerebral calcification - narrow panel v6.10 CMPK2 Sarah Leigh Entity copied from Mitochondrial disorders v8.24
White matter disorders and cerebral calcification - narrow panel v6.10 CMPK2 Sarah Leigh gene: CMPK2 was added
gene: CMPK2 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature,Expert Review Amber
Q2_25_ promote_green tags were added to gene: CMPK2.
Mode of inheritance for gene: CMPK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CMPK2 were set to 33340416; 36443312
Phenotypes for gene: CMPK2 were set to Mitochondrial UMP-CMP kinase 2 deficiency; Developmental delay; Failure to thrive
Mitochondrial disorders v8.24 CMPK2 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: CMPK2.
Mitochondrial disorders v8.24 CMPK2 Sarah Leigh reviewed gene: CMPK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Basal ganglia calcification, idiopathic, 10, autosomal recessive, OMIM:621018, basal ganglia calcification, idiopathic, 10, autosomal recessive, MONDO:0975875; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v8.24 CMPK2 Sarah Leigh Classified gene: CMPK2 as Amber List (moderate evidence)
Mitochondrial disorders v8.24 CMPK2 Sarah Leigh Gene: cmpk2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v8.23 CMPK2 Sarah Leigh Publications for gene: CMPK2 were set to 33340416
Mitochondrial disorders v8.22 CMPK2 Sarah Leigh Publications for gene: CMPK2 were set to PMID: 33340416
Mitochondrial disorders v8.21 ACSL4 Sarah Leigh reviewed gene: ACSL4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mitochondrial disorders v8.21 ACSL4 Sarah Leigh Classified gene: ACSL4 as Red List (low evidence)
Mitochondrial disorders v8.21 ACSL4 Sarah Leigh Gene: acsl4 has been classified as Red List (Low Evidence).
Laterality disorders and isomerism v3.22 AL117258.1 Achchuthan Shanmugasundram Classified gene: AL117258.1 as Amber List (moderate evidence)
Laterality disorders and isomerism v3.22 AL117258.1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (13 unrelated families) for the promotion of this gene to green rating in the next GMS update.
Laterality disorders and isomerism v3.22 AL117258.1 Achchuthan Shanmugasundram Gene: al117258.1 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v3.21 AL117258.1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: AL117258.1.
Laterality disorders and isomerism v3.21 AL117258.1 Achchuthan Shanmugasundram gene: AL117258.1 was added
gene: AL117258.1 was added to Laterality disorders and isomerism. Sources: Literature
Mode of inheritance for gene: AL117258.1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AL117258.1 were set to 34903892; 39513328
Phenotypes for gene: AL117258.1 were set to Heterotaxy, visceral, 12, autosomal, OMIM:619702
Review for gene: AL117258.1 was set to GREEN
Added comment: PMID:34903892 reported the identification of biallelic variants (either homozygous or compound heterozygous ) in the CIROP gene in 21 patients from 12 unrelated families of different geographic origin with congenital heterotaxy. There were a total of nine variants identified in these patients - 5 missense, 2 nonsense, a frameshift, and a small in-frame deletion. The disorder is characterised by defects in the asymmetric positioning of visceral organs across the left-right axis, known as laterality defects. Functional studies performed on Zebrafish and Xenopus knockout models replicated the heterotaxy phenotype. They also showed that CIROP was essential for left side symmetry and is expressed in ciliated left–right organisers.

PMID:39513328 reported a cohort of 24 patients with heterotaxy from 19 unrelated families, of which two patients from a family were identified with homozygous missense CIROP variant.

This gene has been associated with relevant phenotypes in OMIM (MIM #619702), but not in Gene2Phenotype.
Sources: Literature
Hereditary ataxia with onset in adulthood v7.20 DAB1_ATTTC Sarah Leigh Tag nested STR was removed from STR: DAB1_ATTTC.
Undiagnosed metabolic disorders v1.628 GLS_GCA Sarah Leigh Entity copied from Likely inborn error of metabolism v7.21
Undiagnosed metabolic disorders v1.628 GLS_GCA Sarah Leigh STR: GLS_GCA was added
STR: GLS_GCA was added to Undiagnosed metabolic disorders. Sources: Expert Review Red,Literature
STR, NGS Not Validated tags were added to STR: GLS_GCA.
Mode of inheritance for STR: GLS_GCA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: GLS_GCA were set to 30970188
Phenotypes for STR: GLS_GCA were set to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412
Hereditary ataxia with onset in adulthood v7.20 ATXN8OS_CTG Sarah Leigh commented on STR: ATXN8OS_CTG: The numbers of ATXN8OS_CTG required for pathogenicity given by https://stripy.org/database are: 2-37 for normal, 38-79 for intermediate and ≥80 for pathogenic and https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 gives the repeats as follows: ≤ 50 for normal, 38 - 79 for intermediate and ≥ 71 for pathogenic.
Hereditary ataxia with onset in adulthood v7.20 ATXN8OS_CTG Sarah Leigh STR: ATXN8OS_CTG was added
STR: ATXN8OS_CTG was added to Hereditary ataxia with onset in adulthood. Sources: Literature
STR, NGS Not Validated tags were added to STR: ATXN8OS_CTG.
Mode of inheritance for STR: ATXN8OS_CTG was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: ATXN8OS_CTG were set to 16804541; 10192387
Phenotypes for STR: ATXN8OS_CTG were set to Spinocerebellar ataxia 8, OMIM:608768; spinocerebellar ataxia type 8, MONDO:0012116
Review for STR: ATXN8OS_CTG was set to GREEN
Added comment: ATXN8OS transcribed from the forward strand.

ATXN8OS_CTG is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

ATXN8OS_CTG is on https://stripy.org/database

ATXN8OS_CTG is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were obtained from DRAGON 4.02, https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database were 4:39348424-39348485 (hg38)
The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Hereditary ataxia with onset in adulthood v7.19 RFC1_AAGGG Sarah Leigh Publications for STR: RFC1_AAGGG were set to 30926972; 35883251; 36250766; 36289003; 36524104; 36478048
Hereditary ataxia with onset in adulthood v7.18 RFC1_AAGGG Sarah Leigh edited their review of STR: RFC1_AAGGG: Added comment: Pathogenicity at the RFC1_AAGGG repeat locus can result from the biallelic replacement of the benign AAAAG repeat with a variable number of AAGGG repeats (PMID: 30926972; 32040566). Furthermore, biallelic expansions of (AAAAG)exp/(AAAGG)exp, (AAAAG)exp/(AAGGG)exp or (AAAGG)exp/(AAGGG)exp were not pathogenic, therefore, it is the biallelic expansions of AAGGG that is pathogenic (PMID: 30926972). An additional pathogenic biallelic expansion :RFC1_ACAGG, was seen in was seen in two Asia-Pacific CANVAS families and a Japanese case (PMID: 33103729, 35355059).; Changed publications to: 30926972, 35883251, 36250766, 36289003, 36524104, 36478048, 32040566, 33103729, 35355059
Hereditary neuropathy or pain disorder v6.167 RFC1_AAGGG Sarah Leigh Publications for STR: RFC1_AAGGG were set to 30926972; 35883251; 36250766; 36289003; 36524104; 36478048
Hereditary neuropathy or pain disorder v6.166 RFC1_AAGGG Sarah Leigh edited their review of STR: RFC1_AAGGG: Added comment: Pathogenicity at the RFC1_AAGGG repeat locus can result from the biallelic replacement of the benign AAAAG repeat with a variable number of AAGGG repeats (PMID: 30926972; 32040566). Furthermore, biallelic expansions of (AAAAG)exp/(AAAGG)exp, (AAAAG)exp/(AAGGG)exp or (AAAGG)exp/(AAGGG)exp were not pathogenic, therefore, it is the biallelic expansions of AAGGG that is pathogenic (PMID: 30926972). An additional pathogenic biallelic expansion :RFC1_ACAGG, was seen in was seen in two Asia-Pacific CANVAS families and a Japanese case (PMID: 33103729, 35355059).; Changed publications to: 30926972, 35883251, 36250766, 36289003, 36524104, 36478048, 32040566, 33103729, 35355059
Hereditary neuropathy or pain disorder v6.166 RFC1_AAGGG Sarah Leigh STR: RFC1_AAGGG was added
STR: RFC1_AAGGG was added to Hereditary neuropathy or pain disorder. Sources: Literature
STR, NGS Not Validated tags were added to STR: RFC1_AAGGG.
Mode of inheritance for STR: RFC1_AAGGG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: RFC1_AAGGG were set to 30926972; 35883251; 36250766; 36289003; 36524104; 36478048
Phenotypes for STR: RFC1_AAGGG were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM: 614575
Review for STR: RFC1_AAGGG was set to GREEN
Added comment: RFC1 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

RFC1_AAGGG is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

RFC1_AAGGG is on https://stripy.org/database

RFC1_AARRG is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were obtained from DRAGON 4.02 and https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4
The coordinates of the sequence repeats from https://stripy.org/database were 4:39348424-39348485 (hg38)
The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4
And https://stripy.org/database

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Hereditary ataxia with onset in adulthood v7.18 RFC1_AAGGG Sarah Leigh STR: RFC1_AAGGG was added
STR: RFC1_AAGGG was added to Hereditary ataxia with onset in adulthood. Sources: Literature
STR, NGS Not Validated tags were added to STR: RFC1_AAGGG.
Mode of inheritance for STR: RFC1_AAGGG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: RFC1_AAGGG were set to 30926972; 35883251; 36250766; 36289003; 36524104; 36478048
Phenotypes for STR: RFC1_AAGGG were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM: 614575
Review for STR: RFC1_AAGGG was set to GREEN
Added comment: RFC1 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

RFC1_AAGGG is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

RFC1_AAGGG is on https://stripy.org/database

RFC1_AARRG is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were obtained from DRAGON 4.02 and https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4
The coordinates of the sequence repeats from https://stripy.org/database were 4:39348424-39348485 (hg38)
The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4
And https://stripy.org/database

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Thoracic aortic aneurysm or dissection (GMS) v3.20 SMAD6 Sarah Leigh Tag Q2_25_expert_review tag was added to gene: SMAD6.
Hereditary ataxia with onset in adulthood v7.17 DAB1_ATTTC Sarah Leigh Tag nested STR tag was added to STR: DAB1_ATTTC.
Hereditary ataxia with onset in adulthood v7.17 DAB1_ATTTC Sarah Leigh changed review comment from: This is a Nested STR. Pathogenicity is caused by the inclusion of ATTTC repeat (PMID: 29939198; 28686858) within the reference ATTTT repeat. PMID: 28686858 outlined that the pathogenic confirmation of repeats was: [(ATTTT)60–79(ATTTC)31–75(ATTTT)58–90].; to: This is a Nested STR. Pathogenicity is caused by the inclusion of ATTTC repeat (PMID: 29939198; 28686858) within the reference ATTTT repeat. PMID: 28686858 outlined that the pathogenic confirmation of repeats was: [(ATTTT)60–79(ATTTC)31–75(ATTTT)58–90].
Note that DRAGEN 4.02 lists DAB1_ATTTT and not the ATTTC repeat.
Hereditary ataxia with onset in adulthood v7.17 DAB1_ATTTC Sarah Leigh commented on STR: DAB1_ATTTC: This is a Nested STR. Pathogenicity is caused by the inclusion of ATTTC repeat (PMID: 29939198; 28686858) within the reference ATTTT repeat. PMID: 28686858 outlined that the pathogenic confirmation of repeats was: [(ATTTT)60–79(ATTTC)31–75(ATTTT)58–90].
Cerebral vascular malformations v3.26 CCER2 Alexandra Njegic gene: CCER2 was added
gene: CCER2 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: CCER2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CCER2 were set to 27717682
Phenotypes for gene: CCER2 were set to Moyamoya Disease
Penetrance for gene: CCER2 were set to Incomplete
Mode of pathogenicity for gene: CCER2 was set to Other
Review for gene: CCER2 was set to AMBER
Added comment: 27717682: 2 pedigrees (without RNF213 variants), authors identified a delins and a missense variant (one twin unaffected with same missense variant, suggests reduced penetrance). Additional 135 MMD probands sequenced, identified 1 recurrent and an additional 2 in-frame indels (2 probands had RNF213 p.R4810K, and the other had Graves disease). In silico modelling predicts aggregation or oligomerization of CCER2 protein product; insufficient evidence to suggest LOF or GOF.
Sources: Literature
Hereditary ataxia with onset in adulthood v7.17 DAB1_ATTTC Sarah Leigh STR: DAB1_ATTTC was added
STR: DAB1_ATTTC was added to Hereditary ataxia with onset in adulthood. Sources: Literature
STR, NGS Not Validated tags were added to STR: DAB1_ATTTC.
Mode of inheritance for STR: DAB1_ATTTC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: DAB1_ATTTC were set to 29939198; 28686858
Phenotypes for STR: DAB1_ATTTC were set to Spinocerebellar ataxia 37, OMIM: 615945
Review for STR: DAB1_ATTTC was set to GREEN
Added comment: DAB1 is transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

DAB1_ATTTC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

DAB1_ATTTC is on https://stripy.org/database

DAB1_ATTTT is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were the same on:
https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 https://stripy.org/database were 8:118366815-118366913 (hg38) and DRAGON 4.02

The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://stripy.org/database

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Hereditary ataxia with onset in adulthood v7.16 DAB1 Sarah Leigh Phenotypes for gene: DAB1 were changed from Spinocerebellar ataxia 37, 615945; Spinocerebellar ataxia 37 615945 to Spinocerebellar ataxia 37, OMIM: 615945
Cerebral vascular malformations v3.26 SIRT1 Alexandra Njegic gene: SIRT1 was added
gene: SIRT1 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: SIRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIRT1 were set to 30578106
Phenotypes for gene: SIRT1 were set to Vein of Galen Malformation
Penetrance for gene: SIRT1 were set to Incomplete
Review for gene: SIRT1 was set to RED
Added comment: 30578106: 1 family, authors identified 1 de novo frameshift SIRT1 variant in proband, proband also harboured a transmitted CLDN14 variant. Supplementary table suggests relatives have capillary malformations.
Sources: Literature
Thoracic aortic aneurysm or dissection (GMS) v3.20 SMAD6 Sarah Leigh reviewed gene: SMAD6: Rating: RED; Mode of pathogenicity: None; Publications: 39069920, 40133303; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v5.93 SIRT6 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are four foetuses from a single family and several pieces of functional evidence available in support of the association. This gene is tagged for expert review from the Genomic Laboratory Hubs to decide whether the available evidence is sufficient for promotion to green rating on the next update.; to: Comment on list classification: There are four foetuses from a single family and several pieces of functional evidence available in support of the association. This gene is tagged for expert review from the NHS Genomic Medicine Service to decide whether the available evidence is sufficient for promotion to green rating on the next update.
Fetal anomalies v5.93 SIRT6 Achchuthan Shanmugasundram Classified gene: SIRT6 as Amber List (moderate evidence)
Fetal anomalies v5.93 SIRT6 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four foetuses from a single family and several pieces of functional evidence available in support of the association. This gene is tagged for expert review from the Genomic Laboratory Hubs to decide whether the available evidence is sufficient for promotion to green rating on the next update.
Fetal anomalies v5.93 SIRT6 Achchuthan Shanmugasundram Gene: sirt6 has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm or dissection (GMS) v3.20 SMAD6 Sarah Leigh Tag Q2_25_ demote_red tag was added to gene: SMAD6.
Tag Q2_25_ NHS_review tag was added to gene: SMAD6.
Thoracic aortic aneurysm or dissection (GMS) v3.20 SMAD6 Sarah Leigh Publications for gene: SMAD6 were set to 30796334; 28659821; 30963242
Fetal anomalies v5.92 SIRT6 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: SIRT6.
Tag Q2_25_expert_review tag was added to gene: SIRT6.
Fetal anomalies v5.92 SIRT6 Achchuthan Shanmugasundram Phenotypes for gene: SIRT6 were changed from PMID: 29555651 to Fetal anomaly, HP:0034057
Fetal anomalies v5.91 SIRT6 Achchuthan Shanmugasundram Publications for gene: SIRT6 were set to
Fetal anomalies v5.90 SIRT6 Achchuthan Shanmugasundram reviewed gene: SIRT6: Rating: GREEN; Mode of pathogenicity: None; Publications: 29555651, 30135584; Phenotypes: Fetal anomaly, HP:0034057; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v3.26 ITGB1 Alexandra Njegic gene: ITGB1 was added
gene: ITGB1 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: ITGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ITGB1 were set to 37978175
Phenotypes for gene: ITGB1 were set to Vein of Galen Malformation
Penetrance for gene: ITGB1 were set to Incomplete
Review for gene: ITGB1 was set to AMBER
Added comment: 37978175 (including PMID 30578106 cohort): combined 2 probands, 1 unphased frameshift and 1 transmitted splice variant, in silico modelling predicted NMD, pathogenicity given as 'likely damaging'.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v7.26 RAP1B Boaz Palterer gene: RAP1B was added
gene: RAP1B was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: RAP1B was set to Other
Publications for gene: RAP1B were set to 39225097
Phenotypes for gene: RAP1B were set to thrombocytopenia; leukopenia; lymphopenia; anemia; splenomegaly; immunodeficiency; preauricular tag; upslanting palpebral fissures; flat midface; scarce eyebrows; low-set and posteriorly rotated ears; hypoplastic teeth; umbilical hernia, and genitourinary abnormalities; hydronephrosis; vesicoureteral reflux; unilateral cryptorchidism
Penetrance for gene: RAP1B were set to unknown
Mode of pathogenicity for gene: RAP1B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RAP1B was set to GREEN
Added comment: Heterozygous mutation in RAP1B are associated with Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies ( OMIM #620654 ).

Variants have been shown to be gain of function.
Wide spectrum of disease presentation, germline variants associated with full spectrum of disease, reported somatic variants presenting with isolated hematological disease. Varying degree of immunodeficiency, leukopenia and lymphopenia, relevant to this panel.
Sources: Literature
Adult onset leukodystrophy v5.8 CST3 Achchuthan Shanmugasundram Tag Q2_25_ NHS_review tag was added to gene: CST3.
Adult onset neurodegenerative disorder v7.19 CST3 Achchuthan Shanmugasundram Classified gene: CST3 as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v7.19 CST3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >3 unrelated cases with Cerebral amyloid angiopathy (MIM #105150), however they were all reported with the same founder variant.

However, there are 18 patients from ten unrelated families with adult-onset leukodystrophy phenotype (not yet reported in OMIM) and with five different monoallelic variants, of which eight patients from five families were reported with cognitive decline and dementia on or before the age of 55.

Hence, there is sufficient evidence available for the promotion of this gene to green rating on the next GMS update.
Adult onset neurodegenerative disorder v7.19 CST3 Achchuthan Shanmugasundram Gene: cst3 has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v7.18 CST3 Achchuthan Shanmugasundram Phenotypes for gene: CST3 were changed from Cerebral amyloid angiopathy, OMIM:105150 to Cerebral amyloid angiopathy, OMIM:105150; leukodystrophy, MONDO:0019046
Adult onset neurodegenerative disorder v7.17 CST3 Achchuthan Shanmugasundram Publications for gene: CST3 were set to
Adult onset neurodegenerative disorder v7.16 CST3 Achchuthan Shanmugasundram Mode of inheritance for gene: CST3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult onset neurodegenerative disorder v7.15 CST3 Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: CST3.
Adult onset neurodegenerative disorder v7.15 CST3 Achchuthan Shanmugasundram edited their review of gene: CST3: Added comment: PMID:38489591 reported 16 patients from eight families with a novel adult-onset leukodystrophy disorder and with one of four different stop-gain or frameshift monoallelic variants in the CST3 gene. The reported variants are c.360del, c.357+1del, c.340C>T and c.376C>T, and none of these variants are found in general population (gnomAD). Clinical and radiological features of these patients differ markedly from the previously described Icelandic cerebral amyloid angiopathy found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid to older adult ages. Cognitive decline and dementia were present in 11 patients from seven families, of which seven patients from four families were aged below 55.

PMID:38729262 reported two unrelated Chinese individuals with adult-onset leukodystrophy and with monoallelic CST3 variants. One patient had the previously reported c.340C>T variant, while the other had novel c.357+1G>T variant. Memory deterioration and cognitive decline has been noted in the 48-year-old female patient with the novel variant.

This gene has only been reported with Cerebral amyloid angiopathy (MIM #105150) and not yet with the adult-onset leukodystrophy phenotype in OMIM.; Changed rating: GREEN; Changed publications to: 38489591, 38729262; Changed phenotypes to: Cerebral amyloid angiopathy, OMIM:105150, leukodystrophy, MONDO:0019046; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult onset leukodystrophy v5.8 CST3 Achchuthan Shanmugasundram Classified gene: CST3 as Amber List (moderate evidence)
Adult onset leukodystrophy v5.8 CST3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are ten unrelated families reported with a novel adult-onset leukodystrophy disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Adult onset leukodystrophy v5.8 CST3 Achchuthan Shanmugasundram Gene: cst3 has been classified as Amber List (Moderate Evidence).
Adult onset leukodystrophy v5.7 CST3 Achchuthan Shanmugasundram Tag founder-effect was removed from gene: CST3.
Tag Q2_25_ promote_green tag was added to gene: CST3.
Adult onset leukodystrophy v5.7 CST3 Achchuthan Shanmugasundram Phenotypes for gene: CST3 were changed from Cerebral amyloid angiopathy, OMIM:105150; ACys amyloidosis, MONDO:0007098 to leukodystrophy, MONDO:0019046; Cerebral amyloid angiopathy, OMIM:105150; ACys amyloidosis, MONDO:0007098
Adult onset leukodystrophy v5.6 CST3 Achchuthan Shanmugasundram Publications for gene: CST3 were set to 2900981; 3495457; 1352269; 3673496; 7482672; 8108423
Adult onset leukodystrophy v5.5 CST3 Achchuthan Shanmugasundram Mode of inheritance for gene: CST3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult onset leukodystrophy v5.4 CST3 Achchuthan Shanmugasundram reviewed gene: CST3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38489591, 38729262; Phenotypes: leukodystrophy, MONDO:0019046; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia with onset in adulthood v7.15 NEU1 Lauren Turton gene: NEU1 was added
gene: NEU1 was added to Hereditary ataxia with onset in adulthood. Sources: NHS GMS
Mode of inheritance for gene: NEU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEU1 were set to 10944856; 11063730; 32752208; 31371146; 30023283
Phenotypes for gene: NEU1 were set to Ataxia; myoclonus
Review for gene: NEU1 was set to GREEN
gene: NEU1 was marked as current diagnostic
Added comment: NEU1-related sialidosis type I is a milder form of the disorder, characterised by visual defects, macular cherry-red spot, myoclonus, ataxia, and seizures. Onset can be variable from childhood to adulthood. Disorder has been well characterised for many years, with several unrelated patients reported.
Sources: NHS GMS
Ataxia and cerebellar anomalies - narrow panel v7.25 NEU1 Lauren Turton gene: NEU1 was added
gene: NEU1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: NHS GMS
Mode of inheritance for gene: NEU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEU1 were set to 10944856; 11063730; 32752208; 31371146; 30023283
Phenotypes for gene: NEU1 were set to Ataxia; myoclonus
Review for gene: NEU1 was set to GREEN
gene: NEU1 was marked as current diagnostic
Added comment: NEU1-related sialidosis type I is a milder form of the disorder, characterised by visual defects, macular cherry-red spot, myoclonus, ataxia, and seizures. Onset can be variable from childhood to adulthood. Disorder has been well characterised for many years, with several unrelated patients reported.
Sources: NHS GMS
Early onset or syndromic epilepsy v7.90 RNU2-2P Achchuthan Shanmugasundram Classified gene: RNU2-2P as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.90 RNU2-2P Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with epilepsy. Hence, this gene can be promoted to green rating on the next GMS update.
Early onset or syndromic epilepsy v7.90 RNU2-2P Achchuthan Shanmugasundram Gene: rnu2-2p has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.89 RNU2-2P Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: RNU2-2P.
Early onset or syndromic epilepsy v7.89 RNU2-2P Achchuthan Shanmugasundram commented on gene: RNU2-2P: The "new-gene-name" tag has been added as the official HGNC symbol for RNU2-2P is RNU2-2.

In addition, "locus-type-rna-small-nuclear" tag has been added to highlight the biotype for this gene.
Early onset or syndromic epilepsy v7.89 RNU2-2P Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: RNU2-2P.
Tag locus-type-rna-small-nuclear tag was added to gene: RNU2-2P.
Tag dd_review tag was added to gene: RNU2-2P.
Early onset or syndromic epilepsy v7.89 RNU2-2P Achchuthan Shanmugasundram Phenotypes for gene: RNU2-2P were changed from to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v7.88 RNU2-2P Achchuthan Shanmugasundram Publications for gene: RNU2-2P were set to
Early onset or syndromic epilepsy v7.87 RNU2-2P Achchuthan Shanmugasundram Mode of inheritance for gene: RNU2-2P was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v7.86 RNU2-2P Achchuthan Shanmugasundram reviewed gene: RNU2-2P: Rating: GREEN; Mode of pathogenicity: None; Publications: 40210679; Phenotypes: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.242 RNU2-2P Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of this gene with ID and GDD. Hence, this gene can be promoted to green rating on this panel.; to: Comment on list classification: There is sufficient evidence available for the association of this gene with ID and GDD. Hence, this gene can be promoted to green rating on the next GMS update.
Intellectual disability v8.242 RNU2-2P Achchuthan Shanmugasundram Classified gene: RNU2-2P as Amber List (moderate evidence)
Intellectual disability v8.242 RNU2-2P Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with ID and GDD. Hence, this gene can be promoted to green rating on this panel.
Intellectual disability v8.242 RNU2-2P Achchuthan Shanmugasundram Gene: rnu2-2p has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.241 RNU2-2P Achchuthan Shanmugasundram commented on gene: RNU2-2P: The "new-gene-name" tag has been added as the official HGNC symbol for RNU2-2P is RNU2-2.

In addition, "locus-type-rna-small-nuclear" tag has been added to highlight the biotype for this gene.
Intellectual disability v8.241 RNU2-2P Achchuthan Shanmugasundram Tag dd_review tag was added to gene: RNU2-2P.
Tag Q2_25_ promote_green tag was added to gene: RNU2-2P.
Intellectual disability v8.241 RNU2-2P Achchuthan Shanmugasundram Mode of inheritance for gene: RNU2-2P was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.240 RNU2-2P Achchuthan Shanmugasundram Publications for gene: RNU2-2P were set to
Intellectual disability v8.239 RNU2-2P Achchuthan Shanmugasundram Phenotypes for gene: RNU2-2P were changed from to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v8.238 RNU2-2P Achchuthan Shanmugasundram changed review comment from: PMID:40210679 reported nine individuals from 100,000 Genomes Project (100KGP) data in the National Genomic Research Library (NGRL) with a neurodevelopmental disorder and with recurrent de novo single-nucleotide variants at nucleotide positions 4 and 35 of RNU2-2 (n.4G>A & n.35A>G).

Monoallelic variants in this gene were also identified in 16 other cases with neurodevelopmental disorder from eight other rare disease collections. All but two of them were confirmed to have a de novo variant and 15 of them had one of the two variants reported from the 100KGP collection. There were no unaffected carriers of either variant. One case had a different variant at position 35 (35A>C).

Detailed clinical information was provided for 15 of these cases, and the disorder is characterised by intellectual disability (ID), autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases had ID and global developmental delay, and displayed a severe and complex seizure phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:40210679 reported nine individuals from 100,000 Genomes Project (100KGP) data in the National Genomic Research Library (NGRL) with a neurodevelopmental disorder and with recurrent de novo single-nucleotide variants at nucleotide positions 4 and 35 of RNU2-2 (n.4G>A & n.35A>G).

Monoallelic variants in this gene were also identified in 16 other cases with neurodevelopmental disorder from eight other rare disease collections. All but two of them were confirmed to have a de novo variant and 15 of them had one of the two variants reported from the 100KGP collection. There were no unaffected carriers of either variant. One case had a different variant at position 35 (35A>C).

Detailed clinical information was provided for 15 of these cases, and the disorder is characterised by intellectual disability (ID), autistic behaviour, microcephaly, hypotonia, epilepsy and hyperventilation. The phenotype typically manifests from 3 to 6 months of age but is progressive, frequently severe and accompanied by characteristic dysmorphic features. All cases had ID and global developmental delay, and displayed a severe and complex seizure phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v8.238 RNU2-2P Achchuthan Shanmugasundram changed review comment from: PMID:40210679 reported nine individuals from 100,000 Genomes Project (100KGP) data in the National Genomic Research Library (NGRL) with a neurodevelopmental disorder and with recurrent de novo single-nucleotide variants at nucleotide positions 4 and 35 of RNU2-2 (n.4G>A & n.35A>G).

Monoallelic variants in this gene were also identified in 16 other cases with neurodevelopmental disorder from eight other rare disease collections. All but two of them were confirmed to have a de novo variant and 15 of them had one of the two variants reported from the 100KGP collection. There were no unaffected carriers of either variant. One case had a different variant at position 35 (35A>C).

Detailed clinical information was provided for 15 of these cases, and the disorder is characterised by intellectual disability, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:40210679 reported nine individuals from 100,000 Genomes Project (100KGP) data in the National Genomic Research Library (NGRL) with a neurodevelopmental disorder and with recurrent de novo single-nucleotide variants at nucleotide positions 4 and 35 of RNU2-2 (n.4G>A & n.35A>G).

Monoallelic variants in this gene were also identified in 16 other cases with neurodevelopmental disorder from eight other rare disease collections. All but two of them were confirmed to have a de novo variant and 15 of them had one of the two variants reported from the 100KGP collection. There were no unaffected carriers of either variant. One case had a different variant at position 35 (35A>C).

Detailed clinical information was provided for 15 of these cases, and the disorder is characterised by intellectual disability (ID), autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases had ID and global developmental delay, and displayed a severe and complex seizure phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Intellectual disability v8.238 RNU2-2P Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: RNU2-2P.
Tag locus-type-rna-small-nuclear tag was added to gene: RNU2-2P.
Intellectual disability v8.238 RNU2-2P Achchuthan Shanmugasundram reviewed gene: RNU2-2P: Rating: GREEN; Mode of pathogenicity: None; Publications: 40210679; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.238 DDX39B Achchuthan Shanmugasundram Classified gene: DDX39B as Amber List (moderate evidence)
Intellectual disability v8.238 DDX39B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (four unrelated cases with missense variants) available for the association. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v8.238 DDX39B Achchuthan Shanmugasundram Gene: ddx39b has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.237 DDX39B Achchuthan Shanmugasundram changed review comment from: As reviewed by Mike Spiller, PMID:39918047 reported the identification of monoallelic DDX39B variants in six patients from five unrelated families presenting with a neurodevelopmental disorder. Intellectual disability was reported in three of four unrelated patients identified with de novo missense variants, of which ID was severe in two and mild in one. The fourth patient had global developmental delay.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.; to: As reviewed by Mike Spiller, PMID:39918047 reported the identification of monoallelic DDX39B variants in six patients from five unrelated families presenting with a neurodevelopmental disorder. Intellectual disability was reported in three of four unrelated patients identified with de novo missense variants, of which ID was severe in two and mild in one. The fourth patient had global developmental delay.

The two patients from the same family with splice variant did not present with ID.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Intellectual disability v8.237 DDX39B Achchuthan Shanmugasundram changed review comment from: As reviewed by Mike Spiller, PMID:39918047 reported the identification of monoallelic DDX39B variants in six patients from five unrelated families presenting with a neurodevelopmental disorder. Intellectual disability was reported in three of four patients identified with de novo missense variants, of which ID was severe in two and mild in one. The fourth patient had global developmental delay.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.; to: As reviewed by Mike Spiller, PMID:39918047 reported the identification of monoallelic DDX39B variants in six patients from five unrelated families presenting with a neurodevelopmental disorder. Intellectual disability was reported in three of four unrelated patients identified with de novo missense variants, of which ID was severe in two and mild in one. The fourth patient had global developmental delay.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Intellectual disability v8.237 DDX39B Achchuthan Shanmugasundram commented on gene: DDX39B: As reviewed by Mike Spiller, PMID:39918047 reported the identification of monoallelic DDX39B variants in six patients from five unrelated families presenting with a neurodevelopmental disorder. Intellectual disability was reported in three of four patients identified with de novo missense variants, of which ID was severe in two and mild in one. The fourth patient had global developmental delay.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Intellectual disability v8.237 DDX39B Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: DDX39B.
Tag Q2_25_ NHS_review tag was added to gene: DDX39B.
Intellectual disability v8.237 DDX39B Achchuthan Shanmugasundram Phenotypes for gene: DDX39B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v8.236 DDX39B Achchuthan Shanmugasundram Phenotypes for gene: DDX39B were changed from to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v8.236 DDX39B Achchuthan Shanmugasundram Publications for gene: DDX39B were set to PMID: 39918047
Intellectual disability v8.235 DDX39B Achchuthan Shanmugasundram reviewed gene: DDX39B: Rating: GREEN; Mode of pathogenicity: None; Publications: 39918047; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated and arrhythmogenic cardiomyopathy v2.37 TAX1BP3 Achchuthan Shanmugasundram Classified gene: TAX1BP3 as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v2.37 TAX1BP3 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated amber with current evidence as there is only one family and functional work in support of the disease association.
Dilated and arrhythmogenic cardiomyopathy v2.37 TAX1BP3 Achchuthan Shanmugasundram Gene: tax1bp3 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v3.26 KEL Alexandra Njegic gene: KEL was added
gene: KEL was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: KEL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KEL were set to 30578106; 37978175
Phenotypes for gene: KEL were set to Vein of Galen Malformation
Penetrance for gene: KEL were set to unknown
Review for gene: KEL was set to AMBER
Added comment: 37978175, 30578106 (same cohort with additional VOGM probands in 37978175): 30578106; 2/55 VOGM probands with a de novo nonsense or missense variant in KEL, absent in unaffected parents and siblings. No in vitro or in vivo studies. Pathogenicity not provided.
37978175: No additional KEL variants.
Sources: Literature
Hereditary ataxia with onset in adulthood v7.15 BEAN1_TGGAA Sarah Leigh Tag STR tag was added to STR: BEAN1_TGGAA.
Hereditary ataxia with onset in adulthood v7.15 BEAN1_TGGAA Sarah Leigh commented on STR: BEAN1_TGGAA: The repeat sequence TAAAA in BEAN1 is benign and seen in healthy controls. Although the TAAAA repeat is expanded in patients, it is the TGGAA repeat that is pathogenic repeats. The TGGAA repeat is not seen in healthy controls (PMID: 19878914). A further pathogenic repeat was also seen in two cases [TCAC (TGGAA)exp(TAGAA)exp(TAAAA TAGAA)exp] (PMID: 19878914).
Hereditary ataxia with onset in adulthood v7.15 BEAN1_TGGAA Sarah Leigh commented on STR: BEAN1_TGGAA: BEAN1 transcribed from the forward strand.
BEAN1_TGGAA is on https://gnomad.broadinstitute.org/short-tandem-repeat/SAMD12?dataset=gnomad_r4
BEAN1_TGGAA is on https://stripy.org/database
BEAN1_TGGAA is DRAGON 4.02

The coordinates of the sequence repeats shown above were obtained from https://gnomad.broadinstitute.org/short-tandem-repeat/SAMD12?dataset=gnomad_r4 the coordinates were the same on DRAGON 4.02. The coordinates from https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 were 16:66490398-66490453 (hg38)

The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Fetal anomalies v5.90 LMNB2 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: LMNB2.
Tag Q2_25_ NHS_review tag was added to gene: LMNB2.
Severe microcephaly v7.25 LMNB2 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: LMNB2.
Severe microcephaly v7.25 LMNB2 Sarah Leigh changed review comment from: PMID: 40011009 reports two related babies who were homozygous for a loss-of-function LMNB2 variant. Both babies shared a similar phenotype of severe brain development abnormalities and died during the perinatal period. This shared phenotype was reflected in the several Lmnb2-deficient mouse models.
Material from the patient’s fibroblasts (obtained at birth) were used in Western blot and immunofluorescence cell labelling, and confirmed the complete absence of lamin B2 and revealed an increase in lamin B1, together with alterations in alpha-tubulin and vimentin organisation. (PMID: 40011009).; to: PMID: 40011009 reports two related babies who were homozygous for a loss-of-function LMNB2 variant. Both babies shared a similar phenotype of severe brain development abnormalities and died during the perinatal period. This shared phenotype was reflected in several Lmnb2-deficient mouse models.
Material from the patient’s fibroblasts (obtained at birth) were used in Western blot and immunofluorescence cell labelling, and confirmed the complete absence of lamin B2 and revealed an increase in lamin B1, together with alterations in alpha-tubulin and vimentin organisation. (PMID: 40011009).
Fetal anomalies v5.90 LMNB2 Sarah Leigh changed review comment from: PMID: 40011009 reports two related babies who were homozygous for a loss-of-function LMNB2 variant. Both babies shared a similar phenotype of severe brain development abnormalities and died during the perinatal period. This shared phenotype was reflected in the several Lmnb2-deficient mouse models.
Material from the patient’s fibroblasts (obtained at birth) were used in Western blot and immunofluorescence cell labelling, and confirmed the complete absence of lamin B2 and revealed an increase in lamin B1, together with alterations in alpha-tubulin and vimentin organisation. (PMID: 40011009).; to: PMID: 40011009 reports two related babies who were homozygous for a loss-of-function LMNB2 variant. Both babies shared a similar phenotype of severe brain development abnormalities and died during the perinatal period. This shared phenotype was reflected in several Lmnb2-deficient mouse models.
Material from the patient’s fibroblasts (obtained at birth) were used in Western blot and immunofluorescence cell labelling, and confirmed the complete absence of lamin B2 and revealed an increase in lamin B1, together with alterations in alpha-tubulin and vimentin organisation. (PMID: 40011009).
Fetal anomalies v5.90 LMNB2 Sarah Leigh reviewed gene: LMNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Severe microcephaly v7.25 LMNB2 Sarah Leigh edited their review of gene: LMNB2: Added comment: PMID: 40011009 reports two related babies who were homozygous for a loss-of-function LMNB2 variant. Both babies shared a similar phenotype of severe brain development abnormalities and died during the perinatal period. This shared phenotype was reflected in the several Lmnb2-deficient mouse models.
Material from the patient’s fibroblasts (obtained at birth) were used in Western blot and immunofluorescence cell labelling, and confirmed the complete absence of lamin B2 and revealed an increase in lamin B1, together with alterations in alpha-tubulin and vimentin organisation. (PMID: 40011009).; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Severe microcephaly v7.25 LMNB2 Sarah Leigh Phenotypes for gene: LMNB2 were changed from Microcephaly 27, primary, autosomal dominant, OMIM:619180 to Microcephaly 27, primary, autosomal dominant, OMIM:619180; microcephaly 27, primary, autosomal dominant, MONDO:0030929
Fetal anomalies v5.90 LMNB2 Sarah Leigh Phenotypes for gene: LMNB2 were changed from Microcephaly 27, primary, autosomal dominant, OMIM:619180 to Microcephaly 27, primary, autosomal dominant, OMIM:619180; microcephaly 27, primary, autosomal dominant, MONDO:0030929
Severe microcephaly v7.24 LMNB2 Sarah Leigh Publications for gene: LMNB2 were set to 33033404
Fetal anomalies v5.89 LMNB2 Sarah Leigh Publications for gene: LMNB2 were set to 33033404
Cerebral vascular malformations v3.26 CBL Alexandra Njegic reviewed gene: CBL: Rating: GREEN; Mode of pathogenicity: None; Publications: 32637631, 37778001; Phenotypes: Cerebral arteriopathy, Moyamoya Disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cerebral vascular malformations v3.26 DIAPH1 Sarah Leigh Tag watchlist tag was added to gene: DIAPH1.
Cerebral vascular malformations v3.26 DIAPH1 Sarah Leigh Publications for gene: DIAPH1 were set to 34125151; 37400591
Cerebral vascular malformations v3.25 DIAPH1 Sarah Leigh Deleted their comment
Cerebral vascular malformations v3.25 DIAPH1 Sarah Leigh edited their review of gene: DIAPH1: Added comment: Kundishora et al (PMID: 34125151) reports seven DIAPH1 variants in six patients from two cohorts containing a total of 108 patients with features of Moyamoya disease (MMD). The authors suggest that DIAPH1 variants may be associated with MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis. In PMID: 37400591 the authors report that MMD patients with DIAPH1 variants were more likely to have posterior circulation involvement (7/9, 78%) than those without DIAPH1 variants (5/41, 12%). No variant functional studies were presented in these studies.; Changed rating: AMBER
Cerebral vascular malformations v3.25 DIAPH1 Sarah Leigh Added comment: Comment on publications: PMID: 37012328 is not relevant to this gene
Cerebral vascular malformations v3.25 DIAPH1 Sarah Leigh Publications for gene: DIAPH1 were set to 34125151; 37400591; 37012328
Cerebral vascular malformations v3.24 DIAPH1 Sarah Leigh Phenotypes for gene: DIAPH1 were changed from Moyamoya disease to Seizures, cortical blindness, microcephaly syndrome, OMIM:616632; progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, MONDO:0014714
Cerebral vascular malformations v3.23 DIAPH1 Sarah Leigh Classified gene: DIAPH1 as Amber List (moderate evidence)
Cerebral vascular malformations v3.23 DIAPH1 Sarah Leigh Gene: diaph1 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v3.22 ANO1 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: ANO1.
Tag Q2_25_ NHS_review tag was added to gene: ANO1.
Cerebral vascular malformations v3.22 ANO1 Sarah Leigh edited their review of gene: ANO1: Added comment: Three ANO1 variant have been associated with Moyamoya disease 7 (OMIM:620687) in three unrelated cases (PMID: 37253099). Two of the variants were heterozygous in the patients, while the third was homozygous. For each of the variants, electrophysiologic studies in variant transfected HEK293 cells revealed that the variant channel had an increased Ca(2+) sensitivity resulting in increased membrane Cl- conductance at lower intracellular Ca(2+) levels in comparison to the controls, which is consistent with a gain-of-function effect.; Changed rating: GREEN; Changed publications to: 37253099; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cerebral vascular malformations v3.22 ANO1 Sarah Leigh Added comment: Comment on publications: PMID: 37012328 was not relevant to this gene
Cerebral vascular malformations v3.22 ANO1 Sarah Leigh Publications for gene: ANO1 were set to 37253099
Cerebral vascular malformations v3.21 ANO1 Sarah Leigh Publications for gene: ANO1 were set to 37253099; 37012328
Cerebral vascular malformations v3.20 NOS3 Alexandra Njegic changed review comment from: Conflicting reports of mode of inheritance.
37383439: 1/6 Moyamoya disease patients with a NOS3 heterozygous variant, pathogenicity not provided.
36941667: 6 probands from consanguineous parentage with MMA, 2 NOS3 homozygous variants. In vitro studies, splice donor site variant leads to lack of eNOS in endothelial progenitor cells derived from the affected proband. Missense variant leads to reduced eNOS protein expression (HEK cells).
Sources: Literature; to: 2 papers with a different mode of inheritance shown; pathogenicity of AD variant not explored in detail.
37383439: 1/6 Moyamoya disease patients with a NOS3 heterozygous variant, pathogenicity not provided.
36941667: 6 probands from consanguineous parentage with MMA, 2 NOS3 homozygous variants. In vitro studies, splice donor site variant leads to lack of eNOS in endothelial progenitor cells derived from the affected proband. Missense variant leads to reduced eNOS protein expression (HEK cells).
Sources: Literature
Cerebral vascular malformations v3.20 ANO1 Sarah Leigh Phenotypes for gene: ANO1 were changed from Moyamoya disease 7, 620687 to Moyamoya disease 7, OMIM:620687; moyamoya disease 7, MONDO:0958202
Cerebral vascular malformations v3.19 ANO1 Sarah Leigh Classified gene: ANO1 as Amber List (moderate evidence)
Cerebral vascular malformations v3.19 ANO1 Sarah Leigh Gene: ano1 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v3.18 NOS3 Alexandra Njegic gene: NOS3 was added
gene: NOS3 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: NOS3 was set to Other
Publications for gene: NOS3 were set to 37383439; 36941667
Phenotypes for gene: NOS3 were set to Moyamoya Disease; Moyamoya Angiopathy
Penetrance for gene: NOS3 were set to unknown
Review for gene: NOS3 was set to AMBER
Added comment: Conflicting reports of mode of inheritance.
37383439: 1/6 Moyamoya disease patients with a NOS3 heterozygous variant, pathogenicity not provided.
36941667: 6 probands from consanguineous parentage with MMA, 2 NOS3 homozygous variants. In vitro studies, splice donor site variant leads to lack of eNOS in endothelial progenitor cells derived from the affected proband. Missense variant leads to reduced eNOS protein expression (HEK cells).
Sources: Literature
Paediatric disorders - additional genes v6.18 IGFALS Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: IGFALS.
Tag Q2_25_ NHS_review tag was added to gene: IGFALS.
Paediatric disorders - additional genes v6.18 IGFALS Sarah Leigh reviewed gene: IGFALS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric disorders - additional genes v6.18 IGFALS Sarah Leigh Publications for gene: IGFALS were set to
Paediatric disorders - additional genes v6.17 IGFALS Sarah Leigh Phenotypes for gene: IGFALS were changed from short stature to Acid-labile subunit, deficiency of, OMIM:615961; short stature due to primary acid-labile subunit deficiency, MONDO:0014420
Monogenic short stature v1.16 IGFALS Sarah Leigh Phenotypes for gene: IGFALS were changed from Acid-labile subunit, deficiency of, OMIM:615961 to Acid-labile subunit, deficiency of, OMIM:615961; short stature due to primary acid-labile subunit deficiency, MONDO:0014420
Paediatric disorders - additional genes v6.16 IGFALS Sarah Leigh Classified gene: IGFALS as Amber List (moderate evidence)
Paediatric disorders - additional genes v6.16 IGFALS Sarah Leigh Gene: igfals has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v3.18 FOXM1 Alexandra Njegic gene: FOXM1 was added
gene: FOXM1 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: FOXM1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXM1 were set to 38969938
Phenotypes for gene: FOXM1 were set to Moyamoya Disease (Unilateral)
Penetrance for gene: FOXM1 were set to unknown
Review for gene: FOXM1 was set to AMBER
Added comment: 38969938: 1 family, affected father and daughter. In vitro studies with hCMEC/D3 cells overexpressing the variant showed reduced migration and tube formation and increased apoptosis proposed to be due to reduced BCL2 transcription.
Sources: Literature
Hereditary Erythrocytosis v2.13 SH2B3 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: SH2B3.
Tag Q2_25_ NHS_review tag was added to gene: SH2B3.
Hereditary Erythrocytosis v2.13 SH2B3 Sarah Leigh commented on gene: SH2B3: Based on the review by Terri McVeigh (Royal Marsden NHS Foundation Trust), this gene is recommended to be made green.
Hereditary Erythrocytosis v2.13 SH2B3 Sarah Leigh Phenotypes for gene: SH2B3 were changed from Erythrocytosis, somatic, OMIM:133100 to Erythrocytosis, somatic, OMIM:133100; Myelofibrosis, somatic, OMIM:254450; Thrombocythemia, somatic, OMIM:187950
Hereditary Erythrocytosis v2.12 SH2B3 Sarah Leigh Publications for gene: SH2B3 were set to 23812944; 20843259; 34440325; 34021251
Pigmentary skin disorders v3.15 LZTR1 Sarah Leigh reviewed gene: LZTR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39140257, 39258154; Phenotypes: ; Mode of inheritance: None
Cerebral vascular malformations v3.18 EVL Alexandra Njegic gene: EVL was added
gene: EVL was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: EVL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EVL were set to 34125151
Phenotypes for gene: EVL were set to Moyamoya Disease
Penetrance for gene: EVL were set to unknown
Review for gene: EVL was set to RED
Added comment: 34125151: 1 proband with compound heterozygous ‘damaging’ missense variants in EVL, pathogenicity not reported.
No other reports in literature of EVL variants and MMD.
Sources: Literature
Cerebral vascular malformations v3.18 EPHB4 Alexandra Njegic reviewed gene: EPHB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 37978175, 30578106, 29444212, 39367533, 35852613; Phenotypes: Capillary malformation-arteriovenous malformation 2, 618196; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v7.38 NPR3 Eleanor Williams Publications for gene: NPR3 were set to 30032985; 10468599
Skeletal dysplasia v7.37 NPR3 Eleanor Williams Phenotypes for gene: NPR3 were changed from Tall stature; arachnodactyly; extra epiphyses; aortic dilatation to Boudin-Mortier syndrome, OMIM:619543; Boudin-Mortier syndrome, MONDO:0859194
Skeletal dysplasia v7.36 NPR3 Eleanor Williams edited their review of gene: NPR3: Added comment: Additional cases reported in:

PMID: 35233476 - Lauffer et al 2022 - 2 novel compound heterozygous NPR3 variants c.943G>A p.(Ala315Thr) and c.1294A>T p.(Ile432Phe) in a boy with tall stature and macrodactyly of the halluces. The authors note that compared to other patients with NPR-C (encoded by NPR3) loss-of-function, the phenotype appears to be milder.

PMID: 40171685 - Moffat et al 2025 - 3 siblings with a novel homozygous missense variant in NPR3 that in vitro data shows causes loss-of-function. All had tall stature but in addition 1 sibling had severe scoliosis developed and mild scoliosis was observed in the two others. Scoliosis has not been previously reported in NPR3-related tall stature and therefore extends the phenotype.; Changed publications to: 30032985, 10468599, 35233476, 40171685; Changed phenotypes to: Boudin-Mortier syndrome, OMIM:619543
Primary immunodeficiency or monogenic inflammatory bowel disease v7.26 GCC2 Boaz Palterer gene: GCC2 was added
gene: GCC2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: GCC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GCC2 were set to 39813120
Phenotypes for gene: GCC2 were set to NK cell deficiency; recurrent viral infections; immunodeficiency
Penetrance for gene: GCC2 were set to unknown
Review for gene: GCC2 was set to RED
Added comment: Pedroza et al. described 2 patients in two separate kindreds with compound heterozygous GCC2 mutations presenting in childhood with recurrent viral infections, normal NK cell numbers but reduced NK cell function.
During NK cell activation, lytic granules (LGs) converge to the MTOC, enabling precision in cytotoxicity. Pedroza et al. demonstrate that GCC2 maintains convergence via tethering LGs to the Golgi. Absence of GCC2 leads to LG dispersion, non-directed degranulation, and bystander killing, and biallelic missense variants result in human NK cell deficiency.
Sources: Literature
Hereditary ataxia with onset in adulthood v7.15 BEAN1_TGGAA Sarah Leigh STR: BEAN1_TGGAA was added
STR: BEAN1_TGGAA was added to Hereditary ataxia with onset in adulthood. Sources: Literature
NGS Not Validated tags were added to STR: BEAN1_TGGAA.
Mode of inheritance for STR: BEAN1_TGGAA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: BEAN1_TGGAA were set to 19878914
Phenotypes for STR: BEAN1_TGGAA were set to Spinocerebellar ataxia 31, OMIM:117210; spinocerebellar ataxia type 31, MONDO:0007296
Review for STR: BEAN1_TGGAA was set to GREEN
Added comment: Sources: Literature
Pigmentary skin disorders v3.15 LZTR1 Sarah Leigh Publications for gene: LZTR1 were set to 29469822; 25795793
Renal tubulopathies v4.21 ATP6V1B1 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: ATP6V1B1.
Tag Q2_25_ NHS_review tag was added to gene: ATP6V1B1.
Renal tubulopathies v4.21 ATP6V1B1 Sarah Leigh reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39837581, 9916796, 12566520, 18798332; Phenotypes: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, OMIM:267300, renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss, MONDO:0009968; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v4.22 ATP6V1B1 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: ATP6V1B1.
Tag Q2_25_ NHS_review tag was added to gene: ATP6V1B1.
Monogenic hearing loss v4.84 ATP6V1B1 Sarah Leigh Phenotypes for gene: ATP6V1B1 were changed from hearing loss; Distal Renal Tubular Acidosis with Progressive Nerve Deafness; Renal tubular acidosis with deafness, 267300 to Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, OMIM:267300; renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss, MONDO:0009968
Nephrocalcinosis or nephrolithiasis v4.22 ATP6V1B1 Sarah Leigh Phenotypes for gene: ATP6V1B1 were changed from distal renal tubular acidosis; Renal tubular acidosis with deafness 267300 to Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, OMIM:267300; renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss, MONDO:0009968
Nephrocalcinosis or nephrolithiasis v4.21 ATP6V1B1 Sarah Leigh Publications for gene: ATP6V1B1 were set to 39837581
Monogenic hearing loss v4.83 ATP6V1B1 Sarah Leigh Tag Q2_25_ MOI tag was added to gene: ATP6V1B1.
Tag Q2_25_ NHS_review tag was added to gene: ATP6V1B1.
Nephrocalcinosis or nephrolithiasis v4.20 ATP6V1B1 Sarah Leigh reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39837581, 9916796, 12566520, 18798332; Phenotypes: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, OMIM:267300, renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss, MONDO:0009968; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v4.83 ATP6V1B1 Sarah Leigh edited their review of gene: ATP6V1B1: Changed phenotypes to: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, OMIM:267300, renal tubular acidosis, distal, 2, with progressive sensorineural hearing loss, MONDO:0009968
Monogenic hearing loss v4.83 ATP6V1B1 Sarah Leigh reviewed gene: ATP6V1B1: Rating: ; Mode of pathogenicity: None; Publications: 39837581, 9916796, 12566520, 18798332; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v4.20 ATP6V1B1 Sarah Leigh Publications for gene: ATP6V1B1 were set to
Monogenic hearing loss v4.83 ATP6V1B1 Sarah Leigh Publications for gene: ATP6V1B1 were set to PMID:12566520; 1373501; 18798332; 22509993; 2527371; 2869030; 7945239; 9916796
Rare anaemia v3.10 RPL27 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: RPL27.
Tag Q2_25_ NHS_review tag was added to gene: RPL27.
Rare anaemia v3.10 RPL27 Sarah Leigh commented on gene: RPL27: PMID: 25424902 and 38988374 report the de novo occurrence of a RPL27 variant (NM_000988.5(RPL27):c.-2-1G>A) in two unrelated, not ethnically matching cases of Diamond-Blackfan anemia 16 (OMIM:617408). Together with the supportive functional studies in Zebra fish (PMID: 25424902), there is sufficient for RPL27 to be green on this panel.
Cytopenia - NOT Fanconi anaemia v3.39 RPL27 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: RPL27.
Tag Q2_25_ NHS_review tag was added to gene: RPL27.
Cytopenia - NOT Fanconi anaemia v3.39 RPL27 Sarah Leigh reviewed gene: RPL27: Rating: GREEN; Mode of pathogenicity: None; Publications: 25424902, 38988374; Phenotypes: ?Diamond-Blackfan anemia 16, OMIM:617408, Diamond-Blackfan anemia 16, MONDO:0044309; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare anaemia v3.10 RPL27 Sarah Leigh reviewed gene: RPL27: Rating: GREEN; Mode of pathogenicity: None; Publications: 25424902, 38988374; Phenotypes: ?Diamond-Blackfan anemia 16, OMIM:617408, Diamond-Blackfan anemia 16, MONDO:0044309; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v3.39 RPL27 Sarah Leigh Publications for gene: RPL27 were set to 25424902; 38988374
Cytopenia - NOT Fanconi anaemia v3.38 RPL27 Sarah Leigh Phenotypes for gene: RPL27 were changed from Diamond-Blackfan anemia; ?Diamond-Blackfan anemia 16, 617408 to ?Diamond-Blackfan anemia 16, OMIM:617408; Diamond-Blackfan anemia 16, MONDO:0044309
Cytopenia - NOT Fanconi anaemia v3.37 RPL27 Sarah Leigh Publications for gene: RPL27 were set to 25424902
Fetal anomalies v5.88 SCN4A Sarah Leigh Tag Q2_25_ MOI tag was added to gene: SCN4A.
Tag Q2_25_expert_review tag was added to gene: SCN4A.
Fetal anomalies v5.88 SCN4A Sarah Leigh reviewed gene: SCN4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.88 SCN4A Sarah Leigh Phenotypes for gene: SCN4A were changed from PARAMYOTONIA CONGENITA OF VON EULENBURG; HYPERKALEMIC PERIODIC PARALYSIS TYPE 1; HYPOKALEMIC PERIODIC PARALYSIS to Classic congenital myopathy-22A, OMIM:620351; congenital myopathy 22A, classic,MONDO:0957247:Severe fetal congenital myopathy-22B, OMIM:620369; congenital myopathy 22B, severe fetal, MONDO:0957265
Inherited ovarian cancer (without breast cancer) v4.4 LLGL2 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: LLGL2.
Tag Q2_25_ NHS_review tag was added to gene: LLGL2.
Inherited ovarian cancer (without breast cancer) v4.4 LLGL2 Sarah Leigh reviewed gene: LLGL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: High-grade serous ovarian carcinoma; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inherited ovarian cancer (without breast cancer) v4.4 LLGL2 Sarah Leigh Classified gene: LLGL2 as Amber List (moderate evidence)
Inherited ovarian cancer (without breast cancer) v4.4 LLGL2 Sarah Leigh Gene: llgl2 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia v1.338 RAB3A Andrew Mumford changed review comment from: The association between monoallelic variants in RAB3A and cerebellar ataxia was discovered in large-scale gene association study (PMID 36928819).

This was replicated in an extended European case series of 18 affected individuals from 10 families and supported by structural modelling and functional analyses in cell line and Drosophila models. (PMID 40166812).
Sources: Research; to: The association between monoallelic variants in RAB3A and cerebellar ataxia was discovered in large-scale gene association study (PMID 36928819).

This was replicated in an extended European case series of 18 affected individuals from 10 families and supported by structural modelling and functional analyses in cell line and Drosophila models. (PMID 40166812).

Sources: Research
Hereditary ataxia v1.338 RAB3A Andrew Mumford gene: RAB3A was added
gene: RAB3A was added to Hereditary ataxia. Sources: Research
Mode of inheritance for gene: RAB3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB3A were set to PMID:36928819; 40166812
Phenotypes for gene: RAB3A were set to cerebellar ataxia; pyramidal features; neurodevelopmental delay
Penetrance for gene: RAB3A were set to Complete
Review for gene: RAB3A was set to GREEN
Added comment: The association between monoallelic variants in RAB3A and cerebellar ataxia was discovered in large-scale gene association study (PMID 36928819).

This was replicated in an extended European case series of 18 affected individuals from 10 families and supported by structural modelling and functional analyses in cell line and Drosophila models. (PMID 40166812).
Sources: Research
Bilateral congenital or childhood onset cataracts v6.6 HMBS Sharon Whatley gene: HMBS was added
gene: HMBS was added to Bilateral congenital or childhood onset cataracts. Sources: Expert Review
Mode of inheritance for gene: HMBS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMBS were set to 14262853; 1577472; 15534187; 14970743; 31153822
Phenotypes for gene: HMBS were set to 620711; 620704
Penetrance for gene: HMBS were set to Incomplete
Review for gene: HMBS was set to GREEN
Added comment: Biallelic inheritance of HMBS pathogenic variants is very rare. PMID: 14262853 De Villeneuve, 1577472 Llewellyn, 15534187 Solis, 14970743 Hessels and 31153822 Dixon. It has been reported in six children (from 5 families) four children (from 3 families) children have been reported to have cataracts.
PMID: 1577472 Llewellyn reported two siblings with HMBS biallelic pathogenic variants c.499C>T, p.(Arg167Trp) and c.500G>A, p.(Arg167Gln). At the age of 18 months one patient had ataxia with intention tremor and dysarthria secondary to partial agenesis of the cerebella vermis, bilateral cataracts and right optic nerve hypoplasia. Biochemical studies showed excessive excretion of PBG with normal faecal porphyrin and very low erythrocyte PBG deaminase activity. At 3 years of age, she was admitted to hospital following febrile convulsions. When assessed one year later, she had had no further convulsions and no symptoms of acute porphyria. She died at 8 years of age.
PMID: 15534187 Solis reported a 28 month old patient with homozygous HMBS variants c.499C>T, p.(Arg167Trp), bilateral capsular cataracts and a unique pattern of deep cerebral white matter injury, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral grey matter, and infratentorial structures. He had no history of seizures. Neurologic examination confirmed peripheral neuropathy, psychomotor delay and revealed occasional dystonic head positioning and dystonic arm movements. The proband had approximately 1% of normal mean erythrocyte HMBS activity, and urinary ALA and PBG were markedly elevated. He died at 40 months.
PMID: 34089223 Stutterd reported two siblings (45 and 54 years old) with homozygous HMBS variants c.251C > A, p.(Ala84Asp).
Sibling 1, was diagnosed with cataracts at 4 years of age and slowly progressive ataxia at 7. At 36 years, she had spastic/ataxic paraparesis, distal sensory impairment, mild dysarthria, and normal cognitive function. Nerve conduction studies confirmed a mild generalized sensorimotor peripheral neuropathy with reduction in the sural and ulnar sensory nerve action potentials and mild prolongation of F waves in the lower limbs. She was independent. Over a period of 16 months, her ataxia and dysarthria worsened and she underwent liver transplantation which initially gave some improvement after which her neurological function began to decline.
Sibling 2 was diagnosed with cataracts in early childhood and in late childhood, developed slowly progressive ataxia, dysarthria, and mild cognitive impairment. At 53 he had predominantly truncal ataxia and mild peripheral ataxia. He had lower limb spasticity and evidence of a mild peripheral neuropathy.
Both had extensive, mainly confluent, symmetrical signal abnormalities in the periventricular and deep cerebral white matter with relative sparing of the U-fibers. All individuals had bilateral involvement of the thalami with sparing of the basal nuclei, internal capsule, and corpus callosum.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the HMBS gene, due to its low clinical penetrance.
Sources: Expert Review
Childhood onset dystonia, chorea or related movement disorder v6.8 HMBS Sharon Whatley reviewed gene: HMBS: Rating: RED; Mode of pathogenicity: None; Publications: 14262853, 1577472, 15534187, 14970743, 31153822, 15534187; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.165 HMBS Sharon Whatley reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 27539938, 38940544, 35584894, 14262853, 1577472, 15534187, 31153822, 14970743, 34089223, 27558376; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy v1.497 HMBS Sharon Whatley reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27539938, 38940544, 35584894, 14262853, 1577472, 15534187, 31153822, 14970743, 34089223, 27558376; Phenotypes: 176000, 620711, 620704; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Likely inborn error of metabolism v7.21 HMBS Sharon Whatley reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 27539938, 14262853, 1577472, 15534187, 14970743, 27558376, 31153822, 34089223; Phenotypes: 176000, 620711, 620704; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Cerebral vascular malformations v3.18 DIAPH1 Alexandra Njegic gene: DIAPH1 was added
gene: DIAPH1 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: DIAPH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DIAPH1 were set to 34125151; 37400591; 37012328
Phenotypes for gene: DIAPH1 were set to Moyamoya disease
Penetrance for gene: DIAPH1 were set to Incomplete
Mode of pathogenicity for gene: DIAPH1 was set to Other
Review for gene: DIAPH1 was set to AMBER
Added comment: 34125151: Authors suggest MMD risk gene, haploinsufficiency mechanism. Discovery cohort of patients with sporadic, bilateral MMD associated with transfusion dependent thrombocytopenia, found 3/24 variants (2 de novo, 1 transmitted); 4/84 further MMD validation cohort (2 unphased, 1 transmitted). In silico predictions only, no phenotyping of parents. No probands had deafness – AD truncating DIAPH1 associated with deafness 1 with or without thrombocytopenia OMIM: 124900 and AR truncating variants are associated with seizures, cortical blindness, microcephaly syndrome OMIM: 616632.
37400591: 2/50 missense variants (7 synonymous) in an Asian MMD population, authors suggest an association between DIAPH1 mutation and PCA involvement in MMD.
37012328: 3 patients with MMA, DIAPH1 variants identified through WES filtering, no evidence of pathogenicity provided.
Sources: Literature
Undiagnosed metabolic disorders v1.627 HMBS Sharon Whatley reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 27539938, 14262853, 1577472, 15534187, 14970743, 27558376, 31153822, 34089223; Phenotypes: 176000, 620711, 620704; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v7.8 HMBS Sharon Whatley reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 14262853; Phenotypes: 620711, 620704; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cutaneous photosensitivity with a likely genetic cause v3.5 HMBS Sharon Whatley reviewed gene: HMBS: Rating: RED; Mode of pathogenicity: None; Publications: 6962637; Phenotypes: 176000, 620711, 620704; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Inherited white matter disorders v1.184 HMBS Sharon Whatley reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27539938, 31153822, 34089223; Phenotypes: 620711, 620704; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v6.9 HMBS Sharon Whatley changed review comment from: Relevant metabolic investigation: urine porphobilinogen
Although HMBS biallelic pathogenic variants are very rare (8 families worldwide to date) five families have been shown to have white matter anomalies on MRI.
PMID: 15534187 Solis reported a 28 month old patient with homozygous HMBS variants c.499C>T, p.(Arg167Trp), bilateral capsular cataracts and a unique pattern of deep cerebral white matter injury, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral grey matter, and infratentorial structures. He had no history of seizures. Neurologic examination confirmed peripheral neuropathy, psychomotor delay and revealed occasional dystonic head positioning and dystonic arm movements. The proband had approximately 1% of normal mean erythrocyte HMBS activity, and urinary ALA and PBG were markedly elevated. He died at 40 months.
PMID: 27558376 Kevelam reports 3 siblings (between 58, 63 and 57 years old) from a single family see previous review.
PMID: 31153822 Dixon reported an 11 month old patient with biallelic HMBS variants (c.500G > A, p.(Arg167Gln) and c.104C>T, p.(Thr35Met)). At 4-6 weeks of age, he was noted to have developmental delays and later apnoeic episodes. At 3 months he had seizures and feeding difficulty. At 11 months no dysmorphic features were noted. He had an abnormal neurological exam with slight left lower facial droop, hypotonic throughout, absent reflexes in both lower extremities. Magnetic resonance spectroscopy of the brain, revealed an abnormal lactate peak in the cerebral white matter and enlarged bilateral fronto-parietal subarachnoid spaces (BESSI). He had an abnormal electroencephalogram with focal seizure activity but a comprehensive epilepsy panel was negative.
PMID: 34089223 Stutterd reported two siblings see previous review.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the HMBS gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: urine porphobilinogen
Although HMBS biallelic pathogenic variants are very rare (8 families worldwide to date) five families have been shown to have white matter anomalies on MRI.
PMID: 15534187 Solis reported a 28 month old patient with homozygous HMBS variants c.499C>T, p.(Arg167Trp), bilateral capsular cataracts and a unique pattern of deep cerebral white matter injury, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral grey matter, and infratentorial structures. He had no history of seizures. Neurologic examination confirmed peripheral neuropathy, psychomotor delay and revealed occasional dystonic head positioning and dystonic arm movements. The proband had approximately 1% of normal mean erythrocyte HMBS activity, and urinary ALA and PBG were markedly elevated. He died at 40 months.
PMID: 27558376 Kevelam reports 3 siblings (between 58, 63 and 57 years old) from a single family see previous review.
PMID: 31153822 Dixon reported an 11 month old patient with biallelic HMBS variants (c.500G > A, p.(Arg167Gln) and c.104C>T, p.(Thr35Met)). At 4-6 weeks of age, he was noted to have developmental delays and later apnoeic episodes. At 3 months he had seizures and feeding difficulty. At 11 months no dysmorphic features were noted. He had an abnormal neurological exam with slight left lower facial droop, hypotonic throughout, absent reflexes in both lower extremities. Magnetic resonance spectroscopy of the brain, revealed an abnormal lactate peak in the cerebral white matter and enlarged bilateral fronto-parietal subarachnoid spaces (BESSI). He had an abnormal electroencephalogram with focal seizure activity but a comprehensive epilepsy panel was negative.
PMID: 34089223 Stutterd reported two siblings see previous review.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the HMBS gene, due to its low clinical penetrance.
Non-acute porphyrias v1.24 HMBS Sharon Whatley reviewed gene: HMBS: Rating: RED; Mode of pathogenicity: None; Publications: 37540847, 14262853, 1577472, 15534187, 14970743, 27558376, 31153822, 34089223; Phenotypes: 176000, 620711, 620704; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v7.25 HMBS Sharon Whatley changed review comment from: Relevant metabolic investigation: urine porphobilinogen
Although HMBS biallelic pathogenic variants are very rare (8 families worldwide to date) three families (7 individuals) have been shown to have cerebellar ataxia.
PMID: 1577472 Llewellyn reported two siblings with HMBS biallelic pathogenic variants c.499C>T, p.(Arg167Trp) and c.500G>A, p.(Arg167Gln). At the age of 18 months one patient had ataxia with intention tremor and dysarthria secondary to partial agenesis of the cerebella vermis bilateral cataracts and right optic nerve hypoplasia. Biochemical studies showed excessive excretion of PBG with normal faecal porphyrin and very low erythrocyte PBG deaminase activity. At 3 years of age, she was admitted to hospital following febrile convulsions. When assessed one year later, she had had no further convulsions or symptoms of acute porphyria. She died at 8 years of age.
PMID: 15828996 Sheppard reported on the sibling of the above patient. He had no cataracts or other abnormalities with a normal cerebral ultrasound at birth. Urine PBG was raised and erythrocyte PBG-deaminase activity was very low. Developmental progress was normal up to 18 months old. At 10 years of age clinical signs included severe ataxia, peripheral neuropathy and dysarthria. Urinary porphyrins were continuously elevated in this patient.
PMID: 27558376 Kevelam reports 3 siblings with cerebellar ataxia see previous review.
PMID: 34089223 Stutterd reported two siblings and an unrelated patient with ataxia see previous review.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the HMBS gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: urine porphobilinogen
Although HMBS biallelic pathogenic variants are very rare (8 families worldwide to date) three families (7 individuals) have been shown to have cerebellar ataxia.
PMID: 1577472 Llewellyn reported two siblings with HMBS biallelic pathogenic variants c.499C>T, p.(Arg167Trp) and c.500G>A, p.(Arg167Gln). At the age of 18 months one patient had ataxia with intention tremor and dysarthria secondary to partial agenesis of the cerebella vermis, bilateral cataracts and right optic nerve hypoplasia. Biochemical studies showed excessive excretion of PBG with normal faecal porphyrin and very low erythrocyte PBG deaminase activity. At 3 years of age, she was admitted to hospital following febrile convulsions. When assessed one year later, she had had no further convulsions or symptoms of acute porphyria. She died at 8 years of age.
PMID: 15828996 Sheppard reported on the sibling of the above patient. He had no cataracts or other abnormalities with a normal cerebral ultrasound at birth. Urine PBG was raised and erythrocyte PBG-deaminase activity was very low. Developmental progress was normal up to 18 months old. At 10 years of age clinical signs included severe ataxia, peripheral neuropathy and dysarthria. Urinary porphyrins were continuously elevated in this patient.
PMID: 27558376 Kevelam reports 3 siblings with cerebellar ataxia see previous review.
PMID: 34089223 Stutterd reported two siblings and an unrelated patient with ataxia see previous review.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the HMBS gene, due to its low clinical penetrance.
Ataxia and cerebellar anomalies - narrow panel v7.25 HMBS Sharon Whatley reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 1577472, 15828996; Phenotypes: Leukoencephalopathy, HP:0002352, cerebellar ataxia, MONDO:0000437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary Erythrocytosis v2.11 SH2B3 Terri McVeigh reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1182/blood-2024-210339, 10.1016/j.ejcped.2023.100042, PMID: 38024597, PMID: 37981895, https://doi.org/10.1182/blood-2013-08-519843, https://doi.org/10.1016/j.leukres.2024.107566https://doi.org/10.1182/blood-2013-05-500850; Phenotypes: thrombocytosis, myeloproliferative disease, ALL; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cerebral vascular malformations v3.18 ANO1 Alexandra Njegic gene: ANO1 was added
gene: ANO1 was added to Cerebral vascular malformations. Sources: Literature
Mode of inheritance for gene: ANO1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ANO1 were set to 37253099; 37012328
Phenotypes for gene: ANO1 were set to Moyamoya disease 7, 620687
Penetrance for gene: ANO1 were set to Incomplete
Mode of pathogenicity for gene: ANO1 was set to Other
Review for gene: ANO1 was set to AMBER
Added comment: 37253099: 6 families showed AD, 1 patient AR. GOF and LOF implied. 7 variants identified total from 84 unsolved families and additional 150 probands. In vitro modelling of different missense variants in HEK cells shows GOF and LOF mechanisms. GOF variants (p.Met658Val, p.Glu459Lys, p.Thr740Ile p.Glu170Lys) have increased membrane Cl− conductance at lower intracellular Ca2+ levels, determined through patch clamp. Predicted LOF p.Arg890Gln (in gnomAD) as no Ca2+ currents evoked. Some variants show no alteration to Ca2+ sensitivity (p.Arg77Gln [in gnomAD) and p.Ser196Thr) but near binding site for PIP2. Authors note that ANO1 may be paternally imprinted as affected individuals who inherited the variant from their mothers had an earlier age at onset, whereas those who inherited the variant from their father had later onset (families MM137/MM001).
37012328: 88 paediatric MMA patients, 3 patients with mixed clinical presentations had ANO1 variants through WES filtering, no evidence of pathogenicity provided.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v6.9 HMBS Sharon Whatley reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 15534187, 31153822; Phenotypes: Leukoencephalopathy, HP:0002352; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Acute intermittent porphyria v1.1 HMBS Sharon Whatley reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27539938, 38940544, 14262853, 1577472, 15534187, 14970743, 27558376, 31153822, 34089223; Phenotypes: 176000; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v2.36 TAX1BP3 Achchuthan Shanmugasundram Deleted their comment
Dilated and arrhythmogenic cardiomyopathy v2.36 TAX1BP3 Achchuthan Shanmugasundram commented on gene: TAX1BP3: PMID:39963794 reported a kindred with multiple members affected by arrhythmogenic cardiomyopathy (ACM) cosegregating with biallelic TAX1BP3 variants (~28 kb deletion encompassing the entire gene and missense variant p.(Met78Thr)). Three affected siblings from the family had the bialleic variants which were absent in an unaffected sister. Carrier parents were normal.

Experimental work on patient-derived induced pluripotent stem cell cardiac myocytes and a knockout mouse model showed that loss of TAX1BP3 causes calcium dysregulation in cardiomyocytes, which is a known mechanism for arrhythmia.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Dilated and arrhythmogenic cardiomyopathy v2.36 TAX1BP3 Achchuthan Shanmugasundram reviewed gene: TAX1BP3: Rating: AMBER; Mode of pathogenicity: None; Publications: 39963794; Phenotypes: Arrhythmogenic cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v3.37 CFAP46 Achchuthan Shanmugasundram changed review comment from: PMID:29843777 reported a single individual with a heterotaxy syndrome and with a multigenic CNV duplication including CFAP46. This patient also carried a variant in LEFTY1 gene.

PMID:39362668 reported a male patient with compound heterozygous CFAP46 variants and with primary ciliary dyskinesia. The patient presented with chronic respiratory symptoms, bronchiectasis, chronic rhinitis, hearing and ear symptoms, and situs solitus.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.

This gene should be rated red with current evidence.; to: PMID:29843777 reported a single individual with a heterotaxy syndrome and with a multigenic CNV duplication including CFAP46. This patient also carried a variant in LEFTY1 gene.

PMID:39362668 reported a male patient with compound heterozygous CFAP46 variants and with primary ciliary dyskinesia. The patient presented with chronic respiratory symptoms, bronchiectasis, chronic rhinitis, hearing and ear symptoms, and situs solitus.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Respiratory ciliopathies including non-CF bronchiectasis v3.37 CFAP46 Achchuthan Shanmugasundram Phenotypes for gene: CFAP46 were changed from Heterotaxy to primary ciliary dyskinesia, MONDO:0016575
Respiratory ciliopathies including non-CF bronchiectasis v3.36 CFAP46 Achchuthan Shanmugasundram Publications for gene: CFAP46 were set to 29843777
Respiratory ciliopathies including non-CF bronchiectasis v3.35 CFAP46 Achchuthan Shanmugasundram Mode of inheritance for gene: CFAP46 was changed from to BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v3.34 CFAP46 Achchuthan Shanmugasundram reviewed gene: CFAP46: Rating: RED; Mode of pathogenicity: None; Publications: 29843777, 39362668; Phenotypes: primary ciliary dyskinesia, MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v3.34 CFAP221 Achchuthan Shanmugasundram Classified gene: CFAP221 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v3.34 CFAP221 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Steven Cowman, there are two unrelated families reported with biallelic CFAP221 variants and with a PCD phenotype including bronchiectasis. Hence, this gene can be rated amber with current evidence.
Respiratory ciliopathies including non-CF bronchiectasis v3.34 CFAP221 Achchuthan Shanmugasundram Gene: cfap221 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v3.33 CFAP221 Achchuthan Shanmugasundram reviewed gene: CFAP221: Rating: AMBER; Mode of pathogenicity: None; Publications: 31636325, 39362668; Phenotypes: primary ciliary dyskinesia, MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v3.33 CFAP221 Achchuthan Shanmugasundram Publications for gene: CFAP221 were set to 31636325
Early onset or syndromic epilepsy v7.86 STARD7_ATTTC Sarah Leigh commented on STR: STARD7_ATTTC: A long stretch ATTTC repeats is present in conjunction with ATTTT repeats in the intron 1 in the STARD7 gene in patients with OMIM:607876 (Corbett et al. 2019 PMID:31664034). In affected individuals the pathogenic configuration was defined as: (ATTTC)exp(ATTTT )exp. None of the control samples had any repeats of the pathogenic ATTTC motif (PMID:31664034).
Early onset or syndromic epilepsy v7.86 STARD7_ATTTC Sarah Leigh STR: STARD7_ATTTC was added
STR: STARD7_ATTTC was added to Early onset or syndromic epilepsy. Sources: Literature
STR, NGS Not Validated tags were added to STR: STARD7_ATTTC.
Mode of inheritance for STR: STARD7_ATTTC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: STARD7_ATTTC were set to 31664034
Phenotypes for STR: STARD7_ATTTC were set to Epilepsy, familial adult myoclonic, 2, OMIM:607876; epilepsy, familial adult myoclonic, 2, MONDO:0011930
Review for STR: STARD7_ATTTC was set to GREEN
Added comment: STARD7 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

STARD7_ATTTC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

STARD7_ATTTC is on https://stripy.org/database

STARD7_ATTTT is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were the same on DRAGON 4.02, https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database
The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Early onset or syndromic epilepsy v7.85 STARD7 Sarah Leigh Phenotypes for gene: STARD7 were changed from Epilepsy, familial adult myoclonic, 2, 607876; Familial adult myoclonic epilepsy-2; FAME-2 to Epilepsy, familial adult myoclonic, 2, OMIM:607876; epilepsy, familial adult myoclonic, 2, MONDO:0011930
Hereditary neuropathy or pain disorder v6.165 VWA1_GGCGCGGAGC Sarah Leigh Tag STR tag was added to STR: VWA1_GGCGCGGAGC.
Hereditary neuropathy or pain disorder v6.165 VWA1_GGCGCGGAGC Sarah Leigh STR: VWA1_GGCGCGGAGC was added
STR: VWA1_GGCGCGGAGC was added to Hereditary neuropathy or pain disorder. Sources: Literature
NGS Not Validated tags were added to STR: VWA1_GGCGCGGAGC.
Mode of inheritance for STR: VWA1_GGCGCGGAGC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: VWA1_GGCGCGGAGC were set to 33559681
Phenotypes for STR: VWA1_GGCGCGGAGC were set to Neuronopathy, distal hereditary motor, autosomal recessive 7, OMIM:619216; neuronopathy, distal hereditary motor, autosomal recessive 7, MONDO:0030977
Review for STR: VWA1_GGCGCGGAGC was set to GREEN
Added comment: VWA1 is transcribed from the forward strand.

VWA1_GGCGCGGAGC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

VWA1_GGCGCGGAGC is on https://stripy.org/database

VWA1_GGCGCGGAGC is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were the same on the above resources.

The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://stripy.org/database and https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Segmental overgrowth disorders - Deep sequencing v3.19 PADI6 Sarah Leigh Tag Q2_25_ demote_red tag was added to gene: PADI6.
Tag Q2_25_expert_review tag was added to gene: PADI6.
Segmental overgrowth disorders - Deep sequencing v3.19 PADI6 Sarah Leigh edited their review of gene: PADI6: Added comment: Based on review given by Tom Cullup (Great Ormond Street Hospital), PADI6 is not relevant to this panel (Segmental overgrowth disorders - Deep sequencing) and should be demoted to Red. PADI6 variants will be identified using the Multi locus imprinting disorders (R417.2) panel, where this gene is Green.; Changed rating: RED
Polycystic liver disease v1.31 SEC61B Sarah Leigh Tag watchlist tag was added to gene: SEC61B.
Polycystic liver disease v1.31 SEC61B Sarah Leigh reviewed gene: SEC61B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v5.87 LMNB2 Sarah Graham reviewed gene: LMNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 40011009; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Monogenic short stature v1.15 RNPC3 Sarah Leigh reviewed gene: RNPC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Palmoplantar keratodermas v3.27 POMP Arina Puzriakova Deleted their comment
Monogenic short stature v1.15 RNPC3 Sarah Leigh Tag Q2_25_expert_review tag was added to gene: RNPC3.
Monogenic short stature v1.15 RNPC3 Sarah Leigh Tag Q2_25_ demote_red tag was added to gene: RNPC3.
Tag Q2_25_ phenotype tag was added to gene: RNPC3.
Undiagnosed metabolic disorders v1.627 ABCA1 Sarah Leigh Tag Q2_25_ promote_green was removed from gene: ABCA1.
Tag Q2_25_ demote_red was removed from gene: ABCA1.
Tag Q2_25_ MOI was removed from gene: ABCA1.
Tag Q2_25_ demote_amber was removed from gene: ABCA1.
Tag Q2_25_ NHS_review was removed from gene: ABCA1.
Tag Q2_25_ phenotype was removed from gene: ABCA1.
Undiagnosed metabolic disorders v1.627 ABCA1 Sarah Leigh Tag Q2_25_ promote_green tag was added to gene: ABCA1.
Tag Q2_25_ demote_red tag was added to gene: ABCA1.
Tag Q2_25_ MOI tag was added to gene: ABCA1.
Tag Q2_25_ demote_amber tag was added to gene: ABCA1.
Tag Q2_25_ NHS_review tag was added to gene: ABCA1.
Tag Q2_25_ phenotype tag was added to gene: ABCA1.
Respiratory ciliopathies including non-CF bronchiectasis v3.32 CFAP54 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review tag was added to gene: CFAP54.
Respiratory ciliopathies including non-CF bronchiectasis v3.32 CFAP54 Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: CFAP54.
Respiratory ciliopathies including non-CF bronchiectasis v3.32 CFAP54 Achchuthan Shanmugasundram Phenotypes for gene: CFAP54 were changed from to Ciliary dyskinesia, primary, 54, OMIM:621125
Respiratory ciliopathies including non-CF bronchiectasis v3.31 CFAP54 Achchuthan Shanmugasundram Publications for gene: CFAP54 were set to 26224312
Respiratory ciliopathies including non-CF bronchiectasis v3.30 CFAP54 Achchuthan Shanmugasundram Mode of inheritance for gene: CFAP54 was changed from to BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v3.29 CFAP54 Achchuthan Shanmugasundram Classified gene: CFAP54 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v3.29 CFAP54 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Steven Cowman and associated with relevant phenotypes in OMIM (MIM #621125), there is sufficient evidence available (five unrelated families and mouse model) for the promotion of this gene to green rating on the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v3.29 CFAP54 Achchuthan Shanmugasundram Gene: cfap54 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v3.28 CFAP54 Achchuthan Shanmugasundram reviewed gene: CFAP54: Rating: GREEN; Mode of pathogenicity: None; Publications: 37725231, 39362668; Phenotypes: Ciliary dyskinesia, primary, 54, OMIM:621125; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic short stature v1.15 GH1 Sarah Leigh reviewed gene: GH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8496314, 8288694, 8552145, 10689634, 18554279, 17726075; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic short stature v1.15 GH1 Sarah Leigh Tag Q1_25_ NHS_review tag was added to gene: GH1.
Tag Q1_25_ promote_green tag was added to gene: GH1.
Monogenic short stature v1.15 GH1 Sarah Leigh Classified gene: GH1 as Amber List (moderate evidence)
Monogenic short stature v1.15 GH1 Sarah Leigh Gene: gh1 has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.14 GH1 Sarah Leigh Phenotypes for gene: GH1 were changed from Growth hormone deficiency to Growth hormone deficiency, isolated, type IA, OMIM:262400; Growth hormone deficiency, isolated, type IB, OMIM:612781; Growth hormone deficiency, isolated, type II, OMIM:173100; Growth hormone deficiency; Kowarski syndrome, OMIM:262650
Pituitary hormone deficiency v3.15 GH1 Sarah Leigh Phenotypes for gene: GH1 were changed from Growth hormone deficiency, isolated, type II (173100); Growth hormone deficiency, isolated, type IA (262400); Growth hormone deficiency, isolated, type IB (612781) to Growth hormone deficiency, isolated, type IA, OMIM:262400; Growth hormone deficiency, isolated, type IB, OMIM:612781; Growth hormone deficiency, isolated, type II, OMIM:173100
Corneal dystrophy v3.13 TCF4_CTG Sarah Leigh STR: TCF4_CTG was added
STR: TCF4_CTG was added to Corneal dystrophy. Sources: Literature
STR, NGS Not Validated tags were added to STR: TCF4_CTG.
Mode of inheritance for STR: TCF4_CTG was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: TCF4_CTG were set to 29526280; 26401622; 24255041; 25168903; 25722209; 25593321
Phenotypes for STR: TCF4_CTG were set to Corneal dystrophy, Fuchs endothelial, 3, OMIM:613267; corneal dystrophy, Fuchs endothelial, 3, MONDO:0013203
Review for STR: TCF4_CTG was set to GREEN
Added comment: TCF4 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

TCF4_CTG is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

TCF4_CTG is on https://stripy.org/database

TCF4_CTG is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were obtained from DRAGON 4.02
The coordinates https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database were the same as above.

The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://stripy.org/database

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Early onset or syndromic epilepsy v7.84 SAMD12_TTTCA Sarah Leigh changed review comment from: SAMD12 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

SAMD12_TTTCA is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

SAMD12_TTTCA is on https://stripy.org/database

SAMD12_TTTTA is on DRAGON 4.02.

The coordinates and pathogenic ranges of the sequence repeats shown above were obtained from DRAGON 4.02
The coordinates https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database were 8:118366815-118366913 (hg38)

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature; to: SAMD12 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

SAMD12_TTTCA is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

SAMD12_TTTCA is on https://stripy.org/database

SAMD12_TTTTA is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were obtained from DRAGON 4.02
The coordinates https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database were 8:118366815-118366913 (hg38)

The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://stripy.org/database

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Early onset or syndromic epilepsy v7.84 SAMD12_TTTCA Sarah Leigh commented on STR: SAMD12_TTTCA: The TTTCA repeat is present in conjunction with TTTTA repeats in patients with OMIM:601068. Ishiura et al., 2018 (PMID: 29507423). In patients the expansions TTTCA and TTTTA combined was estimated to be in the range of 440 to 3680 repeats (one patient had 598 repeats of TTTTA and 458 repeats of TTTCA). In 82 patients the configuration of expansion was interpreted as: (TTTTA)exp(TTTCA)exp and in one family it was given as: (TTTTA)exp(TTTCA)exp(TTTTA)exp. There were no reports of TTTCA expansions in controls, however, 5.9% of healthy individuals had TTTTA expansions, therefore suggesting that the TTTTA expansion does no contribute to the disease (Ishiura et al., 2018).
Early onset or syndromic epilepsy v7.84 SAMD12_TTTCA Sarah Leigh Mode of inheritance for STR: SAMD12_TTTCA was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.83 SAMD12_TTTCA Sarah Leigh Phenotypes for STR: SAMD12_TTTCA were changed from to Epilepsy, familial adult myoclonic, 1, OMIM:601068; epilepsy, familial adult myoclonic, 1, MONDO:0010985
Early onset or syndromic epilepsy v7.82 SAMD12_TTTCA Sarah Leigh edited their review of STR: SAMD12_TTTCA: Changed rating: GREEN
Early onset or syndromic epilepsy v7.82 SAMD12_TTTCA Sarah Leigh STR: SAMD12_TTTCA was added
STR: SAMD12_TTTCA was added to Early onset or syndromic epilepsy. Sources: Literature
STR, NGS Not Validated tags were added to STR: SAMD12_TTTCA.
Mode of inheritance for STR: SAMD12_TTTCA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: SAMD12_TTTCA were set to 30194086; 29507423; 29939203; 32203200
Review for STR: SAMD12_TTTCA was set to AMBER
Added comment: SAMD12 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

SAMD12_TTTCA is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

SAMD12_TTTCA is on https://stripy.org/database

SAMD12_TTTTA is on DRAGON 4.02.

The coordinates and pathogenic ranges of the sequence repeats shown above were obtained from DRAGON 4.02
The coordinates https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database were 8:118366815-118366913 (hg38)

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Intellectual disability v8.235 KDM5B Tracy Lester reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v3.28 CFAP74 Achchuthan Shanmugasundram Classified gene: CFAP74 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v3.28 CFAP74 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Steven Cowman and associated with relevant phenotypes in OMIM (MIM #620197), there is sufficient evidence available (four unrelated families in total) for the promotion of this gene to green rating on the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v3.28 CFAP74 Achchuthan Shanmugasundram Gene: cfap74 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v3.27 CFAP74 Achchuthan Shanmugasundram Phenotypes for gene: CFAP74 were changed from Primary ciliary dyskinesia; infertility to Ciliary dyskinesia, primary, 49, without situs inversus, OMIM:620197
Respiratory ciliopathies including non-CF bronchiectasis v3.26 CFAP74 Achchuthan Shanmugasundram Publications for gene: CFAP74 were set to 32555313
Respiratory ciliopathies including non-CF bronchiectasis v3.25 CFAP74 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review tag was added to gene: CFAP74.
Tag Q1_25_ promote_green tag was added to gene: CFAP74.
Respiratory ciliopathies including non-CF bronchiectasis v3.25 CFAP74 Achchuthan Shanmugasundram reviewed gene: CFAP74: Rating: GREEN; Mode of pathogenicity: None; Publications: 32555313, 36047773, 39362668; Phenotypes: Ciliary dyskinesia, primary, 49, without situs inversus, OMIM:620197; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.6 DNMT3A Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: DNMT3A.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.6 DNMT3A Sarah Leigh edited their review of gene: DNMT3A: Added comment: Four different DNMT3A variants have so far been associated with carotid paragangliomas in a total of ten cases as part of a syndrome. All of the variants are located within the proline-tryptophan-tryptophan-proline (PWWP) domain of DNMT3A (PMID: 29740169; 33182397; 39166703). De novo occurrence of the DNMT3A variant was proven in one case, one variant was inherited from a mother in another case, three were somatic and the inheritance could not be established in five cases (PMID: 29740169; 33182397; 39166703). The DNMT3A variants had a gain of function mechanism, resulting in hypermethylation of polycomb-marked developmental genes and altered chromatin binding specificity (PMID: 39166703).; Changed rating: GREEN
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.6 DNMT3A Sarah Leigh Publications for gene: DNMT3A were set to 39166703
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.5 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from Heyn-Sproul-Jackson syndrome, OMIM: 618724 to Heyn-Sproul-Jackson syndrome, OMIM: 618724
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.4 DNMT3A Sarah Leigh Added comment: Comment on phenotypes: The patient reported in PMID: 39166703 had Heyn-Sproul-Jackson syndrome (OMIM: 618724), with recurrent carotid paragangliomas.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.4 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from Recurrent carotid paragangliomas to Heyn-Sproul-Jackson syndrome, OMIM: 618724
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.3 DNMT3A Sarah Leigh Phenotypes for gene: DNMT3A were changed from to Recurrent carotid paragangliomas
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.2 DNMT3A Sarah Leigh Classified gene: DNMT3A as Amber List (moderate evidence)
Inherited phaeochromocytoma and paraganglioma excluding NF1 v3.2 DNMT3A Sarah Leigh Gene: dnmt3a has been classified as Amber List (Moderate Evidence).
Hereditary Erythrocytosis v2.11 JAK2 Sarah Leigh Tag Q1_25_ NHS_review tag was added to gene: JAK2.
Tag Q1_25_ MOI tag was added to gene: JAK2.
Tag Q1_25_ promote_green tag was added to gene: JAK2.
Hereditary Erythrocytosis v2.11 JAK2 Sarah Leigh changed review comment from: At least four JAK2 variants have been associated with Hereditary erythrocytosis (PMID: 38629639; 37639050; 27389715). Three biallelic JAK2 variants have been reported in in two unrelated cases (one case being compound heterozygous PMID: 27389715, and the other being homozygous (PMID: 37639050), the forth variant occurs as a heterozygote in the proband, her mother and daughter (PMID: 38629639). All of these four variants have a hyperactivating effect on JAK2/STAT5 signaling pathway (PMID: 38629639; 37639050; 27389715).; to: At least four JAK2 variants have been associated with Hereditary erythrocytosis (PMID: 38629639; 37639050; 27389715). Three biallelic JAK2 variants have been reported in two unrelated cases (one case being compound heterozygous PMID: 27389715, and the other being homozygous (PMID: 37639050), the forth variant occurs as a heterozygote in the proband, her mother and daughter (PMID: 38629639). All of these four variants have a hyperactivating effect on JAK2/STAT5 signaling pathway (PMID: 38629639; 37639050; 27389715).
Hereditary Erythrocytosis v2.11 JAK2 Sarah Leigh Mode of inheritance for gene: JAK2 was changed from Other to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary Erythrocytosis v2.10 JAK2 Sarah Leigh edited their review of gene: JAK2: Added comment: At least four JAK2 variants have been associated with Hereditary erythrocytosis (PMID: 38629639; 37639050; 27389715). Three biallelic JAK2 variants have been reported in in two unrelated cases (one case being compound heterozygous PMID: 27389715, and the other being homozygous (PMID: 37639050), the forth variant occurs as a heterozygote in the proband, her mother and daughter (PMID: 38629639). All of these four variants have a hyperactivating effect on JAK2/STAT5 signaling pathway (PMID: 38629639; 37639050; 27389715).; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed phenotypes to: Hereditary erythrocytosis; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary Erythrocytosis v2.10 JAK2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Functional studies demonstrate that the missense JAK2 variants reported in PMID: 38629639; 37639050; 27389715 all have a gain of funtion.
Hereditary Erythrocytosis v2.10 JAK2 Sarah Leigh Mode of pathogenicity for gene: JAK2 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Hereditary Erythrocytosis v2.9 JAK2 Sarah Leigh Phenotypes for gene: JAK2 were changed from Erythrocytosis, somatic, OMIM:133100; primary familial polycythemia due to EPO receptor mutation, MONDO:0007572 to Hereditary erythrocytosis
Hereditary Erythrocytosis v2.8 JAK2 Sarah Leigh Phenotypes for gene: JAK2 were changed from Erythrocytosis, somatic, OMIM:133100 to Erythrocytosis, somatic, OMIM:133100; primary familial polycythemia due to EPO receptor mutation, MONDO:0007572
Hereditary Erythrocytosis v2.7 JAK2 Sarah Leigh Publications for gene: JAK2 were set to
Segmental overgrowth disorders - Deep sequencing v3.19 PADI6 Tom Cullup reviewed gene: PADI6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Retinal disorders v7.25 C19orf44 Sarah Leigh reviewed gene: C19orf44: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v7.25 C19orf44 Sarah Leigh Phenotypes for gene: C19orf44 were changed from retinal dystrophy; macular dystrophy; cone-rod dystrophy; rod-cone dystrophy to late onset retinal dystrophy
Retinal disorders v7.24 C19orf44 Sarah Leigh Publications for gene: C19orf44 were set to
Retinal disorders v7.23 C19orf44 Sarah Leigh Mode of pathogenicity for gene: C19orf44 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Retinal disorders v7.22 C19orf44 Sarah Leigh Tag Q1_25_ NHS_review tag was added to gene: C19orf44.
Tag Q1_25_ promote_green tag was added to gene: C19orf44.
Retinal disorders v7.22 C19orf44 Sarah Leigh Classified gene: C19orf44 as Amber List (moderate evidence)
Retinal disorders v7.22 C19orf44 Sarah Leigh Gene: c19orf44 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v7.23 SPOUT1 Sarah Leigh changed review comment from: PMID: 39962046 reports the association of biallelic SPOUT1 variants with SPOUT1 Associated Development delay Microcephaly Seizures Short stature. In this study, a total of 18 SPOUT1 variants were found in 28 individuals from 21 unrelated families. Intellectual disability was evident in 10/10 families where it could be ascertained, seizures were reported in 16/21 of the families and short stature was seen in 13/15 families where it could be measured.
SPOUT1 variant zebra fish models showed reduction in larval head size with concomitant apoptosis and the human SPOUT1 missense variants were pathogenic in complementation assays in zebrafish (PMID: 39962046).
Sources: Literature; to: PMID: 39962046 reports the association of biallelic SPOUT1 variants with SPOUT1 Associated Development delay Microcephaly Seizures Short stature. In this study, a total of 18 SPOUT1 variants were found in 28 individuals from 21 unrelated families. Intellectual disability was evident in 10/10 families where it could be ascertained, seizures were reported in 16/21 of the families, short stature was seen in 13/15 families where it could be measured and microcephaly was evident in 18/21 cases, with clearly severe microcephaly in 5 cases (PMID: 39962046, supplementary table 1).
SPOUT1 variant zebra fish models showed reduction in larval head size with concomitant apoptosis and the human SPOUT1 missense variants were pathogenic in complementation assays in zebrafish (PMID: 39962046).
Sources: Literature
Severe microcephaly v7.23 SPOUT1 Sarah Leigh Entity copied from Early onset or syndromic epilepsy v7.81
Severe microcephaly v7.23 SPOUT1 Sarah Leigh gene: SPOUT1 was added
gene: SPOUT1 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
Q1_25_ promote_green tags were added to gene: SPOUT1.
Mode of inheritance for gene: SPOUT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPOUT1 were set to 39962046
Phenotypes for gene: SPOUT1 were set to SPOUT1 Associated Development delay Microcephaly Seizures Short stature
Fetal anomalies v5.87 AL117258.1 Achchuthan Shanmugasundram changed review comment from: The 'new-gene-name' tag has been added as the HGNC approved symbol for this gene is CIROP.; to: The 'new-gene-name' tag has been added as the HGNC approved symbol for this gene is CIROP. This gene was known by the previous symbol LMLN2.
Polycystic liver disease v1.31 SEC61B Bill Griffiths reviewed gene: SEC61B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28375157; Phenotypes: Polycystic liver disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v7.21 THRB Romana Izakovicova reviewed gene: THRB: Rating: GREEN; Mode of pathogenicity: Other; Publications: 37547476; Phenotypes: inherited retinal dystrophy, MONDO:0019118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.235 CLCN7 Arina Puzriakova Added comment: Comment on publications: PMID: 39994654 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.235 CLCN7 Arina Puzriakova Publications for gene: CLCN7 were set to
Intellectual disability v8.234 CLCN7 Arina Puzriakova edited their review of gene: CLCN7: Added comment: PMID: 39994654 (2025) - a novel frameshift variant c.175dupA (p.Met59Asnfs*8) in CLCN7 was identified in a family with suspected ADO-II. The proband was homozygous for the variant and presented with intellectual disability, among features of osteopetrosis, deafness, optic atrophy, hepatosplenomegaly, cleft palate and recurrent infection. The variant showed incomplete penetrance in heterozygous family members.

Intellectual disability does not appear to be a typical feature and therefore maintaining the Red rating for now.; Changed publications to: 39994654
Intellectual disability v8.234 TMLHE Arina Puzriakova Classified gene: TMLHE as Amber List (moderate evidence)
Intellectual disability v8.234 TMLHE Arina Puzriakova Added comment: Comment on list classification: Promoting to Amber as two unrelated families have been reported with moderate ID in association with this gene. This gene is otherwise linked to ASD susceptibility and the phenotype in these families may be explained by the more severe consequence (truncating) of their identified variants.

However, caution should be taken in the future if this gene is being considered for a diagnostic panel as pathogenicity remains unclear and it has been listed as non-disease gene.
Intellectual disability v8.234 TMLHE Arina Puzriakova Gene: tmlhe has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.233 TMLHE Arina Puzriakova Added comment: Comment on publications: PMID: 39845198 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.233 TMLHE Arina Puzriakova Publications for gene: TMLHE were set to 39845198; 23092983
Intellectual disability v8.232 TRMT1L Arina Puzriakova Added comment: Comment on publications: PMID: 39786990 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.232 TRMT1L Arina Puzriakova Publications for gene: TRMT1L were set to 39786990
Intellectual disability v8.231 TMLHE Arina Puzriakova Publications for gene: TMLHE were set to
Intellectual disability v8.230 TMLHE Arina Puzriakova reviewed gene: TMLHE: Rating: ; Mode of pathogenicity: None; Publications: 39845198, 23092983; Phenotypes: {Autism, susceptibility to, X-linked 6}, OMIM:300872; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v8.230 TRMT1L Arina Puzriakova gene: TRMT1L was added
gene: TRMT1L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRMT1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRMT1L were set to 39786990
Phenotypes for gene: TRMT1L were set to Early-onset neurodegenerative symptoms
Added comment: PMID: 39786990 (2025) - using GeneMatcher authors identified two siblings with a homozygous missense variant (c.1535C>T, p.(Pro512Leu)) in TRMT1L. Patients exhibited a range of early-onset neurodegenerative symptoms including intellectual disability, distal motor neuropathy, leukodystrophy, generalized hypotonia, and contractures. The variant segregates with the disease in the family and is predicted to be deleterious based upon multiple pathogenicity prediction algorithms.

Additional evidence required prior to making any conclusions about the pathogenicity of this gene and therefore rating Red for now.
Sources: Literature
Intellectual disability v8.229 KCNJ2 Arina Puzriakova Added comment: Comment on publications: PMID: 22155372 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.229 KCNJ2 Arina Puzriakova Publications for gene: KCNJ2 were set to 22155372
Intellectual disability v8.228 KCNJ2 Arina Puzriakova gene: KCNJ2 was added
gene: KCNJ2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KCNJ2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNJ2 were set to 22155372
Phenotypes for gene: KCNJ2 were set to Short QT syndrome 3, OMIM:609622
Added comment: PMID: 22155372 (2012) - 8-year-old Japanese girl with a markedly short QT interval and a heterozygous KCNJ2 variant (M301K). Authors noted extracardiac features, including severe intellectual disability and seizures, which they suggested might be attributed to the KCNJ2 variant, but they could not exclude the possibility of other mutated genes.

Intellectual disability is not a typical feature and currently there is not enough evidence to conclusively link KCNJ2. Therefore rating Red until more evidence emerges.
Sources: Literature
Ichthyosis and erythrokeratoderma v3.33 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from Arthrogryposis, renal dysfunction, and cholestasis 2 (OMIM:613404) to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404
Ichthyosis and erythrokeratoderma v3.32 VIPAS39 Arina Puzriakova Classified gene: VIPAS39 as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v3.32 VIPAS39 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Ichthyosis and erythrokeratoderma v3.32 VIPAS39 Arina Puzriakova Gene: vipas39 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v3.31 VIPAS39 Arina Puzriakova gene: VIPAS39 was added
gene: VIPAS39 was added to Ichthyosis and erythrokeratoderma. Sources: Literature
Q1_23_promote_green tags were added to gene: VIPAS39.
Mode of inheritance for gene: VIPAS39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VIPAS39 were set to 39736737; 37202112; 32239418; 26019847
Phenotypes for gene: VIPAS39 were set to Arthrogryposis, renal dysfunction, and cholestasis 2 (OMIM:613404)
Review for gene: VIPAS39 was set to GREEN
Added comment: VIPAS39 biallelic variants cause Arthrogryposis, renal dysfunction, and cholestasis 2 (OMIM:613404). At least 11 individuals have been reported in the literature. Ichthyosis is a feature of ARCS and has been reported in at least 7 individuals with VIPAS39 variants (PMID:39736737; 37202112; 32239418; 26019847) which supports inclusion of this gene on the panel.
Sources: Literature
Proteinuric renal disease v4.27 VIPAS39 Arina Puzriakova changed review comment from: VIPAS39 biallelic variants cause Arthrogryposis, renal dysfunction, and cholestasis 2 (OMIM:613404). At least 10 individuals have been reported in the literature. Proteinuria has been reported in at least 8 individuals (PMID:39736737;35151346;37202112;26019847;24071963) which supports inclusion of this gene on the panel.; to: VIPAS39 biallelic variants cause Arthrogryposis, renal dysfunction, and cholestasis 2 (OMIM:613404). At least 11 individuals have been reported in the literature. Proteinuria has been reported in at least 9 individuals (PMID:39736737;35151346;37202112;26019847;24071963;31479177) which supports inclusion of this gene on the panel.
Proteinuric renal disease v4.27 VIPAS39 Arina Puzriakova Publications for gene: VIPAS39 were set to 39736737; 35151346; 37202112; 26019847; 24071963
Proteinuric renal disease v4.26 VIPAS39 Arina Puzriakova Publications for gene: VIPAS39 were set to 20190753
Proteinuric renal disease v4.25 VIPAS39 Arina Puzriakova Classified gene: VIPAS39 as Amber List (moderate evidence)
Proteinuric renal disease v4.25 VIPAS39 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Proteinuric renal disease v4.25 VIPAS39 Arina Puzriakova Gene: vipas39 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v4.24 VIPAS39 Arina Puzriakova Tag Q1_25_ promote_green tag was added to gene: VIPAS39.
Proteinuric renal disease v4.24 VIPAS39 Arina Puzriakova reviewed gene: VIPAS39: Rating: ; Mode of pathogenicity: None; Publications: 39736737, 35151346, 37202112, 26019847, 24071963; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 2 (OMIM:613404); Mode of inheritance: None
Intellectual disability v8.227 VIPAS39 Arina Puzriakova Added comment: Comment on publications: PMID: 39736737 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.227 VIPAS39 Arina Puzriakova Publications for gene: VIPAS39 were set to
Intellectual disability v8.226 VIPAS39 Arina Puzriakova reviewed gene: VIPAS39: Rating: AMBER; Mode of pathogenicity: None; Publications: 39736737, 35151346, 26019847; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v7.21 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from Inherited bleeding disorders; ARC Syndrome (Other metabolic disorders); Arthrogryposis to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404; ARC syndrome
Fetal anomalies v5.87 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from ARTHROGRYPOSIS, RENAL DYSFUNCTION, AND CHOLESTASIS 2 to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404; ARC syndrome
Undiagnosed metabolic disorders v1.627 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from ARC Syndrome (Other metabolic disorders); Arthrogryposis; Inherited bleeding disorders to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404; ARC syndrome; Inherited bleeding disorders
Bleeding and platelet disorders v3.14 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from 613404 Arthrogryposis, renal dysfunction, and cholestasis 2 to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404; ARC syndrome
Arthrogryposis v8.7 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from Arthrogryposis, renal dysfunction, and cholestasis 2, 613404; arthrogryposis, renal dysfunction and cholestasis syndrome (ARC) to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404; ARC syndrome
Unexplained kidney failure in young people v1.120 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from Arthrogryposis, renal dysfunction, and cholestasis 2, 613404 to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404; ARC syndrome
Inherited bleeding disorders v1.179 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from ARC syndrome (Arthrogryposis, renal dysfunction, and cholestasis 1) to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404; ARC syndrome
Cholestasis v3.7 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from Arthrogryposis, Renal Dysfunction, and Cholestasis 2; ARC syndrome; Arthrogryposis-renal-cholestasis syndrome; Neonatal and Adult Cholestasis; Arthrogryposis, renal dysfunction, and cholestasis 2, 613404 to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404; ARC syndrome
Neonatal cholestasis v1.27 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from Neonatal and Adult Cholestasis; Arthrogryposis, renal dysfunction, and cholestasis 2, 613404; Arthrogryposis, Renal Dysfunction, and Cholestasis 2; ARC syndrome; Arthrogryposis-renal-cholestasis syndrome to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404; ARC syndrome
Proteinuric renal disease v4.24 VIPAS39 Arina Puzriakova Mode of inheritance for gene: VIPAS39 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.226 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from Gene2Phenotype confirmed gene with ID HPO to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404
Proteinuric renal disease v4.23 VIPAS39 Arina Puzriakova Phenotypes for gene: VIPAS39 were changed from Arthrogryposis, renal dysfunction, and cholestasis 2 # 613404 to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM:613404
Intellectual disability v8.225 WT1 Arina Puzriakova Added comment: Comment on publications: PMID: 39625990 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.225 WT1 Arina Puzriakova Publications for gene: WT1 were set to
Intellectual disability v8.224 WT1 Arina Puzriakova reviewed gene: WT1: Rating: ; Mode of pathogenicity: None; Publications: 39625990; Phenotypes: Denys-Drash syndrome, OMIM:194080; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v8.224 FUT2 Arina Puzriakova Added comment: Comment on publications: PMID: 39350204 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.224 FUT2 Arina Puzriakova Publications for gene: FUT2 were set to 39350204
Early onset or syndromic epilepsy v7.81 FUT2 Arina Puzriakova Added comment: Comment on publications: PMID: 39350204 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.81 FUT2 Arina Puzriakova Publications for gene: FUT2 were set to 39350204
Rare anaemia v3.10 FUT2 Arina Puzriakova Added comment: Comment on publications: PMID: 39350204 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Rare anaemia v3.10 FUT2 Arina Puzriakova Publications for gene: FUT2 were set to 39350204
Rare anaemia v3.9 FUT2 Arina Puzriakova gene: FUT2 was added
gene: FUT2 was added to Rare anaemia. Sources: Literature
Mode of inheritance for gene: FUT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUT2 were set to 39350204
Phenotypes for gene: FUT2 were set to Developmental and epileptic encephalopathy
Added comment: PMID: 39350204 (2024) - homozygous missense variant (NC_000019.10:g.48703291C>T) in the FUT2 gene was identified in an infant with vitamin B12-responsive developmental and epileptic encephalopathy and megaloblastic anemia. Although the mechanism of how the FUT2 gene variant affects vitamin B12 absorption is unclear.

Additional evidence is required before conclusively implicating FUT2 in human disease and therefore rating Red for now.
Sources: Literature
Intellectual disability v8.223 FUT2 Arina Puzriakova gene: FUT2 was added
gene: FUT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FUT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUT2 were set to 39350204
Phenotypes for gene: FUT2 were set to Developmental and epileptic encephalopathy
Added comment: PMID: 39350204 (2024) - homozygous missense variant (NC_000019.10:g.48703291C>T) in the FUT2 gene was identified in an infant with vitamin B12-responsive developmental and epileptic encephalopathy and megaloblastic anemia. Although the mechanism of how the FUT2 gene variant affects vitamin B12 absorption is unclear.

Additional evidence is required before conclusively implicating FUT2 in human disease and therefore rating Red for now.
Sources: Literature
Early onset or syndromic epilepsy v7.80 FUT2 Arina Puzriakova gene: FUT2 was added
gene: FUT2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: FUT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUT2 were set to 39350204
Phenotypes for gene: FUT2 were set to Developmental and epileptic encephalopathy
Added comment: PMID: 39350204 (2024) - homozygous missense variant (NC_000019.10:g.48703291C>T) in the FUT2 gene was identified in an infant with vitamin B12-responsive developmental and epileptic encephalopathy and megaloblastic anemia. Although the mechanism of how the FUT2 gene variant affects vitamin B12 absorption is unclear.

Additional evidence is required before conclusively implicating FUT2 in human disease and therefore rating Red for now.
Sources: Literature
Early onset or syndromic epilepsy v7.79 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from Epilepsy, progressive myoclonic 2A (Lafora) 254780 to Myoclonic epilepsy of Lafora 1, OMIM:254780
Childhood onset dystonia, chorea or related movement disorder v6.8 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from to Myoclonic epilepsy of Lafora 1, OMIM:254780
Likely inborn error of metabolism v7.20 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from Epilepsy, progressive myoclonic 2A (Lafora) to Myoclonic epilepsy of Lafora 1, OMIM:254780
Hereditary ataxia with onset in adulthood v7.14 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from Progressive myoclonic epilepsy 2A, Lafora, 254780; Epilepsy, progressive myoclonic 2A (Lafora) 254780 to Myoclonic epilepsy of Lafora 1, OMIM:254780
Undiagnosed metabolic disorders v1.626 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from Epilepsy, progressive myoclonic 2A (Lafora) 254780 to Myoclonic epilepsy of Lafora 1, OMIM:254780
Adult onset neurodegenerative disorder v7.15 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from Epilepsy, progressive myoclonic 2A (Lafora), OMIM:254780 to Myoclonic epilepsy of Lafora 1, OMIM:254780
Hereditary ataxia v1.338 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from Epilepsy, progressive myoclonic 2A (Lafora) 254780 to Myoclonic epilepsy of Lafora 1, OMIM:254780
Glycogen storage disease v2.5 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from Epilepsy, progressive myoclonic 2A (Lafora) 254780 to Myoclonic epilepsy of Lafora 1, OMIM:254780
Ataxia and cerebellar anomalies - narrow panel v7.25 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from Epilepsy, progressive myoclonic 2A (Lafora) to Myoclonic epilepsy of Lafora 1, OMIM:254780
Intellectual disability v8.222 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from Epilepsy, progressive myoclonic 2A (Lafora) 254780 to Myoclonic epilepsy of Lafora 1, OMIM:254780
Intellectual disability v8.221 EPM2A Arina Puzriakova Added comment: Comment on publications: PMID: 39385815 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.221 EPM2A Arina Puzriakova Publications for gene: EPM2A were set to 21376300
Intellectual disability v8.220 EPM2A Arina Puzriakova reviewed gene: EPM2A: Rating: ; Mode of pathogenicity: None; Publications: 39385815; Phenotypes: ; Mode of inheritance: None
Intellectual disability v8.220 TFG Sarah Leigh Classified gene: TFG as Amber List (moderate evidence)
Intellectual disability v8.220 TFG Sarah Leigh Gene: tfg has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.219 TFG Sarah Leigh edited their review of gene: TFG: Added comment: Biallelic TFG variants have been associated with Spastic paraplegia 57, autosomal recessive (OMIM:615658). Five biallelic TFG variants have been associated with OMIM:615658 in nine families from various ethnicities (PMID: 23479643; 27601211; 27492651; 28124177; 29971521; 30467354; 33767317). A range of phenotypic features were reported (table 2 in PMID: 33767317), with spasticity apparent in 8/8 families examined and intellectual disability in 5/9 families.; Changed rating: GREEN
Intellectual disability v8.219 TFG Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: TFG.
Intellectual disability v8.219 TFG Sarah Leigh Publications for gene: TFG were set to 23479643; 33767317
Intellectual disability v8.218 TFG Sarah Leigh Publications for gene: TFG were set to 33767317
Intellectual disability v8.217 TFG Sarah Leigh Added comment: Comment on publications: PMID: 33767317 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.217 TFG Sarah Leigh Publications for gene: TFG were set to 33767317
Paediatric disorders - additional genes v6.15 DET1 Sarah Leigh Added comment: Comment on publications: PMID: 39937864 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Paediatric disorders - additional genes v6.15 DET1 Sarah Leigh Publications for gene: DET1 were set to 39937864
Fetal anomalies v5.86 DET1 Sarah Leigh Added comment: Comment on publications: PMID: 39937864 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Fetal anomalies v5.86 DET1 Sarah Leigh Publications for gene: DET1 were set to 39937864
Fetal anomalies v5.85 DET1 Sarah Leigh gene: DET1 was added
gene: DET1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DET1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DET1 were set to 39937864
Phenotypes for gene: DET1 were set to neurological defects and lethality
Review for gene: DET1 was set to RED
Added comment: PMID: 39937864 reports a family where the three affected siblings were homozygous for a variant in DET1 (c.76C>T, p.R26W) and also for a variant in COMMD4 (c.122T>G; p.L41R). These genes are both on chromosome 15, separated by 13 Mb and are likely to co-segregate. The parents of these cases were healthy, heterozygous carriers of the DET1 p.R26W variant. The cases described developed lethal developmental abnormalities and the longest lived sib died at 8 months old. Extensive functional studies were reported in PMID: 39937864 and using Det1-
deficient mice and human-induced pluripotent stem cells (iPSCs) expressing DET1R26W,
the authors were able to show that DET1 is essential for normal neuronal development.
Sources: Literature
Paediatric disorders - additional genes v6.14 DET1 Sarah Leigh gene: DET1 was added
gene: DET1 was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: DET1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DET1 were set to 39937864
Phenotypes for gene: DET1 were set to neurological defects and lethality
Review for gene: DET1 was set to RED
Added comment: PMID: 39937864 reports a family where the three affected siblings were homozygous for a variant in DET1 (c.76C>T, p.R26W) and also for a variant in COMMD4 (c.122T>G; p.L41R). These genes are both on chromosome 15, separated by 13 Mb and are likely to co-segregate. The parents of these cases were healthy, heterozygous carriers of the DET1 p.R26W variant. The cases described developed lethal developmental abnormalities and the longest lived sib died at 8 months old. Extensive functional studies were reported in PMID: 39937864 and using Det1-
deficient mice and human-induced pluripotent stem cells (iPSCs) expressing DET1R26W,
the authors were able to show that DET1 is essential for normal neuronal development.
Sources: Literature
Malformations of cortical development v7.3 DLGAP4 Arina Puzriakova Added comment: Comment on publications: PMID:35585091 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Malformations of cortical development v7.3 DLGAP4 Arina Puzriakova Publications for gene: DLGAP4 were set to 35585091
Malformations of cortical development v7.2 DLGAP4 Arina Puzriakova gene: DLGAP4 was added
gene: DLGAP4 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: DLGAP4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLGAP4 were set to 35585091
Review for gene: DLGAP4 was set to RED
Added comment: PMID: 35585091 (2022) - patient with a de novo variant in DLGAP4 gene was identified (family P616; c.2714_2715insCAGCTGG, N905Qfs). Clinical presentation included extensive subependymal heterotopia, cerebral paralysis, GDD (without ID), spastic diplegia. In an additional family (P477), heterozygous variants were also observed in twins - a paternally inherited missense variant in DLGAP4 (c.2893T>G, p.Ser965Ala) and maternally inherited missense variant in DLGAP1 (c.1397A>G, p.Asp466Gly). The twins presented with DD and parieto-occipital pachygyria.

Functional studies show that DLGAP4 plays a role in maintaining the progenitor pool, regulating neurogenesis and neuronal migration.

Overall more evidence is required before drawing conclusions about the role of DLGAP4 in human disease.
Sources: Literature
Intellectual disability v8.216 YBX3 Arina Puzriakova Added comment: Comment on publications: PMID:39423228 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.216 YBX3 Arina Puzriakova Publications for gene: YBX3 were set to 39423228
Intellectual disability v8.215 YBX3 Arina Puzriakova gene: YBX3 was added
gene: YBX3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: YBX3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: YBX3 were set to 39423228
Phenotypes for gene: YBX3 were set to Neurological disorder
Review for gene: YBX3 was set to RED
Added comment: PMID: 39423228 (2024) - functional studies in C. elegans indicate that the Y-Box (YBX) RBP family are involved in memory and cognitive processes. Based on this finding, authors identified two unrelated individuals in the Baylor Genetics dataset with the same heterozygous VUS (c.379A>T (p.Asn127Tyr)) in the YBX3 gene and neurological symptoms. However, phenotypic overlap was limited and there was also a third family with the same variant and a metabolic phenotype. Modelling this variant in worms did lead to memory deficits, however given the clinical heterogeneity among human carriers, there is not enough evidence to draw any conclusions about this gene.
Sources: Literature
Adult onset neurodegenerative disorder v7.14 SGIP1 Arina Puzriakova Added comment: Comment on publications: PMID:39332416 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Adult onset neurodegenerative disorder v7.14 SGIP1 Arina Puzriakova Publications for gene: SGIP1 were set to 39332416
Adult onset neurodegenerative disorder v7.13 SGIP1 Arina Puzriakova gene: SGIP1 was added
gene: SGIP1 was added to Adult onset neurodegenerative disorder. Sources: Literature
Mode of inheritance for gene: SGIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGIP1 were set to 39332416
Phenotypes for gene: SGIP1 were set to Early-onset parkinsonism
Added comment: PMID: 39332416 (2024) - consanguineous Arab family with two affected sisters who manifested young-onset parkinsonism (onset at age 19 and 22). Other features include intellectual/cognitive dysfunction, behavioral problems, and seizures (in one individual). WES revealed a homozygous missense variant (c.2080T>G (p.W694G)) in the SGIP1 gene. Functional studies in Drosophila demonstrated movement defects, synaptic transmission dysfunction, and neurodegeneration, including dopaminergic synapse loss.

Rating Red as only a single family has been reported to date.
Sources: Literature
Mitochondrial disorders v8.20 NDUFA3 Arina Puzriakova Added comment: Comment on publications: PMID:39661167 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Mitochondrial disorders v8.20 NDUFA3 Arina Puzriakova Publications for gene: NDUFA3 were set to
Likely inborn error of metabolism v7.19 NDUFA3 Arina Puzriakova Added comment: Comment on publications: PMID:39661167 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Likely inborn error of metabolism v7.19 NDUFA3 Arina Puzriakova Publications for gene: NDUFA3 were set to
Possible mitochondrial disorder - nuclear genes v3.123 NDUFA3 Arina Puzriakova Added comment: Comment on publications: PMID:39661167 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Possible mitochondrial disorder - nuclear genes v3.123 NDUFA3 Arina Puzriakova Publications for gene: NDUFA3 were set to 39661167
Mitochondrial disorder with complex I deficiency v3.15 NDUFA3 Arina Puzriakova Added comment: Comment on publications: PMID:39661167 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Mitochondrial disorder with complex I deficiency v3.15 NDUFA3 Arina Puzriakova Publications for gene: NDUFA3 were set to 39661167
Mitochondrial disorders v8.19 NDUFA3 Arina Puzriakova Phenotypes for gene: NDUFA3 were changed from Isolated complex I deficiency; No OMIM phenotype to Leigh syndrome
Likely inborn error of metabolism v7.18 NDUFA3 Arina Puzriakova Phenotypes for gene: NDUFA3 were changed from No OMIM phenotype; Isolated complex I deficiency to Leigh syndrome
Possible mitochondrial disorder - nuclear genes v3.122 NDUFA3 Arina Puzriakova Phenotypes for gene: NDUFA3 were changed from No OMIM phenotype to Leigh syndrome
Mitochondrial disorder with complex I deficiency v3.14 NDUFA3 Arina Puzriakova Phenotypes for gene: NDUFA3 were changed from No OMIM phenotype to Leigh syndrome
Mitochondrial disorders v8.18 NDUFA3 Arina Puzriakova Mode of inheritance for gene: NDUFA3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v7.17 NDUFA3 Arina Puzriakova Mode of inheritance for gene: NDUFA3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.121 NDUFA3 Arina Puzriakova Publications for gene: NDUFA3 were set to
Mitochondrial disorder with complex I deficiency v3.13 NDUFA3 Arina Puzriakova Publications for gene: NDUFA3 were set to
Possible mitochondrial disorder - nuclear genes v3.120 NDUFA3 Arina Puzriakova Mode of inheritance for gene: NDUFA3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v3.12 NDUFA3 Arina Puzriakova Mode of inheritance for gene: NDUFA3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.119 NDUFA3 Arina Puzriakova reviewed gene: NDUFA3: Rating: ; Mode of pathogenicity: None; Publications: 39661167; Phenotypes: Leigh syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v8.17 NDUFA3 Arina Puzriakova reviewed gene: NDUFA3: Rating: ; Mode of pathogenicity: None; Publications: 39661167; Phenotypes: Leigh syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v7.16 NDUFA3 Arina Puzriakova reviewed gene: NDUFA3: Rating: ; Mode of pathogenicity: None; Publications: 39661167; Phenotypes: Leigh syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v3.11 NDUFA3 Arina Puzriakova reviewed gene: NDUFA3: Rating: ; Mode of pathogenicity: None; Publications: 39661167; Phenotypes: Leigh syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v7.21 IDH3G Sarah Leigh Classified gene: IDH3G as Amber List (moderate evidence)
Retinal disorders v7.21 IDH3G Sarah Leigh Gene: idh3g has been classified as Amber List (Moderate Evidence).
Retinal disorders v7.20 IDH3G Sarah Leigh gene: IDH3G was added
gene: IDH3G was added to Retinal disorders. Sources: Literature
Q1_25_ promote_green tags were added to gene: IDH3G.
Mode of inheritance for gene: IDH3G was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: IDH3G were set to 40119724
Phenotypes for gene: IDH3G were set to X-linked retinitis pigmentosa
Review for gene: IDH3G was set to GREEN
Added comment: PMID: 40119724 reports four hemizygous IDH3G single nucleotide variants (SNVs) in males with a X-linked retinitis pigmentosa. A further case was reported with a 25kb deletion, which encompassed the entire IDH3G gene, but also included PLXNB3 and SRPK3 genes. In all cases the IDH3G variant segregated with the disease, this was confirmed by sequencing in two of the families (figure 1 in PMID: 40119724). Functional studies showed that the IDH3G SNVs reduced expression of the IDH3G.
Sources: Literature
Adult onset dystonia, chorea or related movement disorder v4.10 XK Arina Puzriakova Classified gene: XK as Amber List (moderate evidence)
Adult onset dystonia, chorea or related movement disorder v4.10 XK Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Adult onset dystonia, chorea or related movement disorder v4.10 XK Arina Puzriakova Gene: xk has been classified as Amber List (Moderate Evidence).
Adult onset dystonia, chorea or related movement disorder v4.9 XK Arina Puzriakova Deleted their comment
Adult onset dystonia, chorea or related movement disorder v4.9 XK Arina Puzriakova Added comment: Comment on publications: PMID:39315078 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Adult onset dystonia, chorea or related movement disorder v4.9 XK Arina Puzriakova Publications for gene: XK were set to 8619554; 21714011; 11761473; 17469188; 23192927; 37720304; 34487382; 35977449; 24098554; 39315078
Adult onset dystonia, chorea or related movement disorder v4.8 XK Arina Puzriakova Classified gene: XK as Amber List (moderate evidence)
Adult onset dystonia, chorea or related movement disorder v4.8 XK Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to green at the next GMS panel update.
Adult onset dystonia, chorea or related movement disorder v4.8 XK Arina Puzriakova Gene: xk has been classified as Amber List (Moderate Evidence).
Adult onset dystonia, chorea or related movement disorder v4.7 XK Arina Puzriakova gene: XK was added
gene: XK was added to Adult onset dystonia, chorea or related movement disorder. Sources: Literature
Q1_25_ promote_green tags were added to gene: XK.
Mode of inheritance for gene: XK was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: XK were set to 8619554; 21714011; 11761473; 17469188; 23192927; 37720304; 34487382; 35977449; 24098554; 39315078
Phenotypes for gene: XK were set to McLeod syndrome, OMIM:300842
Review for gene: XK was set to GREEN
Added comment: Numerous variants have been reported in cases of McLeod syndrome (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).

McLeod syndrome causes a multi-system disorder. The presentation can resemble Huntington Disease. Typically primary manifestations are neurological (e.g. chorea, tics, parkinsonism, dystonia, seizures) and muscular (myopathy, peripheral neuropathy), some patients also exhibited cognitive issues, psychiatric symptoms (psychosis, delusions, depression, obsessive-compulsive features), and emotional lability.

Onset is typically in the 4th decade of life and therefore appropriate for this panel.
Sources: Literature
Retinal disorders v7.19 AP5B1 Sarah Leigh Phenotypes for gene: AP5B1 were changed from Macular dystrophy to Lysosomal macular dystrophy
Retinal disorders v7.18 AP5B1 Sarah Leigh Publications for gene: AP5B1 were set to PMID 40081374
Retinal disorders v7.17 AP5B1 Sarah Leigh Classified gene: AP5B1 as Amber List (moderate evidence)
Retinal disorders v7.17 AP5B1 Sarah Leigh Gene: ap5b1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v7.16 AP5B1 Sarah Leigh reviewed gene: AP5B1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Retinal disorders v7.16 AP5M1 Sarah Leigh reviewed gene: AP5M1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Retinal disorders v7.16 AP5M1 Sarah Leigh Tag Q1_25_ NHS_review tag was added to gene: AP5M1.
Tag Q1_25_ promote_green tag was added to gene: AP5M1.
Retinal disorders v7.16 AP5M1 Sarah Leigh Phenotypes for gene: AP5M1 were changed from to Lysosomal macular dystrophy
Retinal disorders v7.15 AP5M1 Sarah Leigh Publications for gene: AP5M1 were set to
Retinal disorders v7.14 AP5M1 Sarah Leigh Classified gene: AP5M1 as Amber List (moderate evidence)
Retinal disorders v7.14 AP5M1 Sarah Leigh Gene: ap5m1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v7.13 AP5Z1 Sarah Leigh changed review comment from: In PMID: 40081374, Kaminska et al report variants in three of the genes which encode different subunits of the vesicular fifth adaptor protein (AP-5) complex: AP5Z1, AP5M1, and AP5B1, in patients with a specific form of macular degeneration. Seventeen biallelic AP5Z1 variants were been reported in fourteen unrelated families with macular degeneration. Due to the involvement of variants in the AP-5 complex, the authors suggest that the resultant condition should be called lysosomal macular dystrophy.; to: In PMID: 40081374, Kaminska et al report variants in three of the genes which encode different subunits of the vesicular fifth adaptor protein (AP-5) complex: AP5Z1, AP5M1, and AP5B1, in patients with a specific form of macular degeneration. Seventeen biallelic AP5Z1 variants were been reported in fourteen unrelated families, three homozygous AP5M1 variant were found in three unrelated cases and three biallelic AP5B1 variants were found in two unrelated cases. Due to the involvement of variants in the AP-5 complex, the authors suggest that the resultant condition should be called lysosomal macular dystrophy.
Retinal disorders v7.13 AP5Z1 Sarah Leigh reviewed gene: AP5Z1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Retinal disorders v7.13 AP5Z1 Sarah Leigh Phenotypes for gene: AP5Z1 were changed from Hereditary lysosomal macular dystrophy to Lysosomal macular dystrophy
Retinal disorders v7.12 AP5Z1 Sarah Leigh Phenotypes for gene: AP5Z1 were changed from Hereditary macular dystrophy to Hereditary lysosomal macular dystrophy
Retinal disorders v7.11 AP5Z1 Sarah Leigh Phenotypes for gene: AP5Z1 were changed from Macular dystrophy to Hereditary macular dystrophy
Retinal disorders v7.10 AP5Z1 Sarah Leigh Tag Q1_25_ NHS_review tag was added to gene: AP5Z1.
Tag Q1_25_ promote_green tag was added to gene: AP5Z1.
Retinal disorders v7.10 AP5Z1 Sarah Leigh Classified gene: AP5Z1 as Amber List (moderate evidence)
Retinal disorders v7.10 AP5Z1 Sarah Leigh Gene: ap5z1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v7.9 AP5Z1 Sarah Leigh Publications for gene: AP5Z1 were set to PMID: 40081374
Intellectual disability v8.214 ABI2 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39774290 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

PMID:39774290 is a secondary publication and the relevant case described in this publication was originally from the primary publication PMID:28397838.
Intellectual disability v8.214 ABI2 Achchuthan Shanmugasundram Publications for gene: ABI2 were set to 28397838; 39774290
Intellectual disability v8.213 ABI2 Achchuthan Shanmugasundram gene: ABI2 was added
gene: ABI2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ABI2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABI2 were set to 28397838; 39774290
Phenotypes for gene: ABI2 were set to intellectual disability, MONDO:0001071
Review for gene: ABI2 was set to RED
Added comment: PMID:28397838 reported the identification of variants in a cohort of 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID by combining microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES). This study identified a patient with homozygous loss-of-function variant in ABI2 gene (p.(Arg132Ter)).

This gene has not yet been associated with phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.212 CYFIP1 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39774290 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

PMID:39774290 is a secondary publication and the relevant case described in this publication was originally from the primary publication PMID:37704042.
Intellectual disability v8.212 CYFIP1 Achchuthan Shanmugasundram Publications for gene: CYFIP1 were set to 37704042; 39774290
Intellectual disability v8.211 CYFIP1 Achchuthan Shanmugasundram gene: CYFIP1 was added
gene: CYFIP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CYFIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYFIP1 were set to 37704042; 39774290
Phenotypes for gene: CYFIP1 were set to intellectual disability, MONDO:0001071
Review for gene: CYFIP1 was set to RED
Added comment: PMID:37704042 reported two individuals from a family with intellectual disability, autism spectrum disorder, spastic tetraparesis, and brain morphology defects. They were identified with compound heterozygous missense variants in the CYFIP1 gene (p.(Ile476Val) and p.(Pro742Leu)).

Functional work from patient fibroblasts showed deficits in actin polymerization. In addition, Drosophila knockin models for these variants exhibited abnormal brain morphology and F-actin loss, and recapitulated the core behavioural symptoms, such as deficits in social interaction and motor coordination.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v7.26 TLR8 Anastasia Vasiliki Madenidou reviewed gene: TLR8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34981838; Phenotypes: haemolytic anaemia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency or monogenic inflammatory bowel disease v7.26 TMEM173 Anastasia Vasiliki Madenidou reviewed gene: TMEM173: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25401470; Phenotypes: systemic lupus erythematosus; Mode of inheritance: None
Intellectual disability v8.210 C1QC Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39196411 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.210 C1QC Achchuthan Shanmugasundram Publications for gene: C1QC were set to 39196411
Intellectual disability v8.209 C1QC Achchuthan Shanmugasundram gene: C1QC was added
gene: C1QC was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: C1QC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1QC were set to 39196411
Phenotypes for gene: C1QC were set to C1q deficiency 3, OMIM:620322
Review for gene: C1QC was set to RED
Added comment: PMID:39196411 reported 12 patients with C1q deficiency, of which one was identified with homozygous variant in C1QC gene (p.(Arg69Ter)). Intellectual impairment was reported in this patient.
Sources: Literature
Intellectual disability v8.208 C1QA Achchuthan Shanmugasundram changed review comment from: Comment on publications: PMID:39196411 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques; to: Comment on publications: PMID:39196411 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.208 C1QA Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39196411 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v8.208 C1QA Achchuthan Shanmugasundram Publications for gene: C1QA were set to 39196411
Intellectual disability v8.207 C1QA Achchuthan Shanmugasundram gene: C1QA was added
gene: C1QA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: C1QA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1QA were set to 39196411
Phenotypes for gene: C1QA were set to C1q deficiency 1, OMIM:613652
Review for gene: C1QA was set to RED
Added comment: PMID:39196411 reported 12 patients with C1q deficiency, of which 10 of them were identified with homozygous variants in C1QA gene. Global developmental delay was reported in only one of these ten cases.
Sources: Literature
Intellectual disability v8.206 TFG Sarah Leigh Publications for gene: TFG were set to
Intellectual disability v8.205 ATAD2B Arina Puzriakova commented on gene: ATAD2B: PMID: 39313616 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.205 ATAD2B Arina Puzriakova gene: ATAD2B was added
gene: ATAD2B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATAD2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD2B were set to 39313616
Phenotypes for gene: ATAD2B were set to intellectual disability, MONDO:0001071
Added comment: PMID: 39313616 - two unrelated individuals were identified with biallelic variants in the ATAD2B gene. One patient had an affected sibling with the same genotype and a similar phenotype. A fourth individual with biallelic variants was also identified in GeneDx. All had developmental delay or cognitive impairment but otherwise had distinct phenotypes (with exception of the sibs) (summary in Supplementary Table 6).

Given the lack of phenotypic overlap, more evidence is required to implicate ATAD2B and therefore rating Red until more evidence emerges.
Sources: Literature
Distal myopathies v6.4 GIPC1_GGC Sarah Leigh STR: GIPC1_GGC was added
STR: GIPC1_GGC was added to Distal myopathies. Sources: Literature
STR, NGS Not Validated tags were added to STR: GIPC1_GGC.
Mode of inheritance for STR: GIPC1_GGC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: GIPC1_GGC were set to 32413282; 33374016
Phenotypes for STR: GIPC1_GGC were set to Oculopharyngodistal myopathy 2, OMIM:618940
Review for STR: GIPC1_GGC was set to GREEN
Added comment: GIPC1 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

GIPC1_GGC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

GIPC1_GGC is on https://stripy.org/database

GIPC1_GGC is on DRAGON 4.02.

The coordinates and pathogenic ranges of the sequence repeats were obtained from
https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3 and were the same on https://stripy.org/database and DRAGON 4.02

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v7.24 ZFHX3_GGC Sarah Leigh edited their review of STR: ZFHX3_GGC: Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v7.24 ZFHX3_GGC Sarah Leigh STR: ZFHX3_GGC was added
STR: ZFHX3_GGC was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
STR, NGS Not Validated tags were added to STR: ZFHX3_GGC.
Mode of inheritance for STR: ZFHX3_GGC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for STR: ZFHX3_GGC were set to Spinocerebellar ataxia 4, OMIM:600223
Review for STR: ZFHX3_GGC was set to AMBER
Added comment: ZFHX3 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

ZFHX3_GGC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

ZFHX3_GGC is on https://stripy.org/database

ZFHX3_GGC is not on DRAGON 4.02.

The coordinates and pathogenic ranges of the sequence repeats were obtained from
https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3 and were the same on https://stripy.org/database

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Intellectual disability v8.204 ASCC3 Arina Puzriakova Tag Q1_25_ promote_green tag was added to gene: ASCC3.
Intellectual disability v8.204 ASCC3 Arina Puzriakova commented on gene: ASCC3: PMID: 39286456 (2024) - three additional unrelated families identified with biallelic variants in the ASCC3 gene. All affected individuals had developmental delay and muscle fatigue. Other features included intellectual disability, hypotonia, motor impairment, feeding difficulties, and proximal/truncal muscle weakness.

Review of all reported cases (21 individuals) to date showed clinical heterogeneity, however most patients did exhibit intellectual disability of varying severity which can be the main presenting feature. Overall this supports inclusion of this gene on the panel.
Congenital myopathy v5.16 ASCC3 Arina Puzriakova Publications for gene: ASCC3 were set to 21937992; 35047834
Intellectual disability v8.204 ASCC3 Arina Puzriakova Added comment: Comment on publications: PMID: 39286456 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.204 ASCC3 Arina Puzriakova Publications for gene: ASCC3 were set to 21937992; 26350204; https://doi.org/10.1016/j.xhgg.2021.100024
Mitochondrial disorders v8.17 SUPV3L1 Sarah Leigh Classified gene: SUPV3L1 as Amber List (moderate evidence)
Mitochondrial disorders v8.17 SUPV3L1 Sarah Leigh Gene: supv3l1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.203 SUPV3L1 Sarah Leigh Classified gene: SUPV3L1 as Amber List (moderate evidence)
Intellectual disability v8.203 SUPV3L1 Sarah Leigh Gene: supv3l1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.202 SUPV3L1 Sarah Leigh edited their review of gene: SUPV3L1: Changed rating: GREEN
Intellectual disability v8.202 SUPV3L1 Sarah Leigh changed review comment from: Three SUPV3L1 variants have been reported in two unrelated cases with a syndrome that includes ataxia, spasticity, optic atrophy and skin hypopigmentation (ASOASH) and also intellectual disability (PMID: 35023579;39596606).
The homozygous terminating SUPV3L1 variant (NM_003171.3: c.2215C>T, p.Gln739*) reported in the siblings in PMID: 35023579, was shown to results in reduced expression of the truncated protein in the proband's fibroblasts, resulting in a reduction of the mature ND6 mRNA species and also the accumulation of double-stranded RNA. This effect was partly restored using full-length SUPV3L1 cDNA (PMID: 35023579). This variant and the compound heterozygous SUPV3L1 variants (NM_003171.5: c.272-2A>G and c.1924A>C; p.(Ser642Arg) reported in PMID: 39596606 were each inherited from the parents of the proband (PMID: 35023579;39596606).
Sources: Literature; to: Three SUPV3L1 variants have been reported in two unrelated cases with a syndrome that includes ataxia, spasticity, optic atrophy and skin hypopigmentation (ASOASH) and also intellectual disability (PMID: 35023579;39596606).
The homozygous terminating SUPV3L1 variant (NM_003171.3: c.2215C>T, p.Gln739*) reported in the siblings in PMID: 35023579, was shown to results in reduced expression of the truncated protein in the proband's fibroblasts, resulting in a reduction of the mature ND6 mRNA species and also the accumulation of double-stranded RNA. This effect was partly restored using full-length SUPV3L1 cDNA (PMID: 35023579). This variant and the compound heterozygous SUPV3L1 variants (NM_003171.5: c.272-2A>G and c.1924A>C; p.(Ser642Arg) reported in PMID: 39596606 were each inherited from the parents of the proband (PMID: 35023579;39596606). Supportive functional studies were presented in PMID: 35023579 and 39596606.
Sources: Literature
Mitochondrial disorders v8.16 SUPV3L1 Sarah Leigh edited their review of gene: SUPV3L1: Changed rating: GREEN
Mitochondrial disorders v8.16 SUPV3L1 Sarah Leigh changed review comment from: Three SUPV3L1 variants have been reported in two unrelated cases with a syndrome that includes ataxia, spasticity, optic atrophy and skin hypopigmentation (ASOASH) and also intellectual disability (PMID: 35023579;39596606).
The homozygous terminating SUPV3L1 variant (NM_003171.3: c.2215C>T, p.Gln739*) reported in the siblings in PMID: 35023579, was shown to results in reduced expression of the truncated protein in the proband's fibroblasts, resulting in a reduction of the mature ND6 mRNA species and also the accumulation of double-stranded RNA. This effect was partly restored using full-length SUPV3L1 cDNA (PMID: 35023579). This variant and the compound heterozygous SUPV3L1 variants (NM_003171.5: c.272-2A>G and c.1924A>C; p.(Ser642Arg) reported in PMID: 39596606 were each inherited from the parents of the proband (PMID: 35023579;39596606).
Sources: Literature; to: Three SUPV3L1 variants have been reported in two unrelated cases with a syndrome that includes ataxia, spasticity, optic atrophy and skin hypopigmentation (ASOASH) and also intellectual disability (PMID: 35023579;39596606).
The homozygous terminating SUPV3L1 variant (NM_003171.3: c.2215C>T, p.Gln739*) reported in the siblings in PMID: 35023579, was shown to results in reduced expression of the truncated protein in the proband's fibroblasts, resulting in a reduction of the mature ND6 mRNA species and also the accumulation of double-stranded RNA. This effect was partly restored using full-length SUPV3L1 cDNA (PMID: 35023579). This variant and the compound heterozygous SUPV3L1 variants (NM_003171.5: c.272-2A>G and c.1924A>C; p.(Ser642Arg) reported in PMID: 39596606 were each inherited from the parents of the proband (PMID: 35023579;39596606). Supportive functional studies were presented in PMID: 35023579 and 39596606.
Sources: Literature
Mitochondrial disorders v8.16 SUPV3L1 Sarah Leigh Added comment: Comment on publications: PMID: 39596606 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Mitochondrial disorders v8.16 SUPV3L1 Sarah Leigh Publications for gene: SUPV3L1 were set to 35023579; 39596606
Intellectual disability v8.202 SUPV3L1 Sarah Leigh Added comment: Comment on publications: PMID: 39596606 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.202 SUPV3L1 Sarah Leigh Publications for gene: SUPV3L1 were set to 35023579; 39596606
Mitochondrial disorders v8.15 SUPV3L1 Sarah Leigh gene: SUPV3L1 was added
gene: SUPV3L1 was added to Mitochondrial disorders. Sources: Literature
Q1_25_ promote_green tags were added to gene: SUPV3L1.
Mode of inheritance for gene: SUPV3L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUPV3L1 were set to 35023579; 39596606
Phenotypes for gene: SUPV3L1 were set to Mitochondrial RNA Helicase SUPV3L1-Associated neurodegenerative syndrome
Review for gene: SUPV3L1 was set to AMBER
Added comment: Three SUPV3L1 variants have been reported in two unrelated cases with a syndrome that includes ataxia, spasticity, optic atrophy and skin hypopigmentation (ASOASH) and also intellectual disability (PMID: 35023579;39596606).
The homozygous terminating SUPV3L1 variant (NM_003171.3: c.2215C>T, p.Gln739*) reported in the siblings in PMID: 35023579, was shown to results in reduced expression of the truncated protein in the proband's fibroblasts, resulting in a reduction of the mature ND6 mRNA species and also the accumulation of double-stranded RNA. This effect was partly restored using full-length SUPV3L1 cDNA (PMID: 35023579). This variant and the compound heterozygous SUPV3L1 variants (NM_003171.5: c.272-2A>G and c.1924A>C; p.(Ser642Arg) reported in PMID: 39596606 were each inherited from the parents of the proband (PMID: 35023579;39596606).
Sources: Literature
Intellectual disability v8.201 SUPV3L1 Sarah Leigh gene: SUPV3L1 was added
gene: SUPV3L1 was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: SUPV3L1.
Mode of inheritance for gene: SUPV3L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUPV3L1 were set to 35023579; 39596606
Phenotypes for gene: SUPV3L1 were set to Mitochondrial RNA Helicase SUPV3L1-Associated neurodegenerative syndrome
Review for gene: SUPV3L1 was set to AMBER
Added comment: Three SUPV3L1 variants have been reported in two unrelated cases with a syndrome that includes ataxia, spasticity, optic atrophy and skin hypopigmentation (ASOASH) and also intellectual disability (PMID: 35023579;39596606).
The homozygous terminating SUPV3L1 variant (NM_003171.3: c.2215C>T, p.Gln739*) reported in the siblings in PMID: 35023579, was shown to results in reduced expression of the truncated protein in the proband's fibroblasts, resulting in a reduction of the mature ND6 mRNA species and also the accumulation of double-stranded RNA. This effect was partly restored using full-length SUPV3L1 cDNA (PMID: 35023579). This variant and the compound heterozygous SUPV3L1 variants (NM_003171.5: c.272-2A>G and c.1924A>C; p.(Ser642Arg) reported in PMID: 39596606 were each inherited from the parents of the proband (PMID: 35023579;39596606).
Sources: Literature
Intellectual disability v8.200 MARS2 Achchuthan Shanmugasundram changed review comment from: Comment on publications: PMID:39995633 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

The patient reported in PMID:39995633 presented with psychomotor developmental delay, growth failure, and generalized skeletal alterations. Genetic analyses showed novel biallelic variants, c.277G > A; p.(Asp93Asn) and c.409C > T; p.(Arg137Cys) in the MARS2 gene. These variants were inherited from the patient's parents, with one variant detected in the mother and the other in the father, both heterozygous.; to: Comment on publications: PMID:39995633 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

The patient reported in PMID:39995633 presented with psychomotor developmental delay, growth failure, and generalized skeletal alterations. However, this patient was not reported with intellectual disability in the publication.

Genetic analyses showed novel biallelic variants, c.277G > A; p.(Asp93Asn) and c.409C > T; p.(Arg137Cys) in the MARS2 gene. These variants were inherited from the patient's parents, with one variant detected in the mother and the other in the father, both heterozygous.
Intellectual disability v8.200 MARS2 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39995633 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

The patient reported in PMID:39995633 presented with psychomotor developmental delay, growth failure, and generalized skeletal alterations. Genetic analyses showed novel biallelic variants, c.277G > A; p.(Asp93Asn) and c.409C > T; p.(Arg137Cys) in the MARS2 gene. These variants were inherited from the patient's parents, with one variant detected in the mother and the other in the father, both heterozygous.
Intellectual disability v8.200 MARS2 Achchuthan Shanmugasundram Publications for gene: MARS2 were set to 25754315
Intellectual disability v8.199 MARS2 Achchuthan Shanmugasundram reviewed gene: MARS2: Rating: RED; Mode of pathogenicity: None; Publications: 39995633; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.199 HNRNPC Achchuthan Shanmugasundram Classified gene: HNRNPC as Amber List (moderate evidence)
Intellectual disability v8.199 HNRNPC Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (14 unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v8.199 HNRNPC Achchuthan Shanmugasundram Gene: hnrnpc has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.198 HNRNPC Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:40004505 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.198 HNRNPC Achchuthan Shanmugasundram Publications for gene: HNRNPC were set to 37541189; 40004505
Intellectual disability v8.197 HNRNPC Achchuthan Shanmugasundram changed review comment from: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterized by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterised by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.197 HNRNPC Achchuthan Shanmugasundram gene: HNRNPC was added
gene: HNRNPC was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: HNRNPC.
Mode of inheritance for gene: HNRNPC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPC were set to 37541189; 40004505
Phenotypes for gene: HNRNPC were set to Intellectual developmental disorder, autosomal dominant 74, OMIM:620688
Review for gene: HNRNPC was set to GREEN
Added comment: PMID:37541189 reported a cohort of 13 individuals with heterozygous germline variants in HNRNPC gene, including a recurrent de novo in-frame deletion in five individuals (c.850_876del/ p.(Arg284_Asp292del) for HNRNPC-iso1 and c.889_915del/ p.(Arg297_Asp305del) for HNRNPC-iso2). They all presented with a neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and subtle facial dysmorphic features in most individuals.

PMID:40004505 reported the identification of the missense variant, p.(Arg99Gln) in a patient showing a unique clinical presentation characterized by DD/ID, distinctive facial features, cochlear aplasia, and bilateral colobomatous microphthalmia. This variant was previously reported in an individual in PMID:37541189. The clinical phenotype of this individual fit that of the previously described individual and only partially overlaps with the clinical spectrum of the disease.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620688), but not yet in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v7.78 KCNH8 Sarah Leigh Added comment: Comment on publications: PMID: 39156922 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.78 KCNH8 Sarah Leigh Publications for gene: KCNH8 were set to 39156922
Early onset or syndromic epilepsy v7.77 RTEL1 Sarah Leigh Added comment: Comment on publications: PMID: 39156922 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.77 RTEL1 Sarah Leigh Publications for gene: RTEL1 were set to 39156922
Early onset or syndromic epilepsy v7.76 RTEL1 Sarah Leigh gene: RTEL1 was added
gene: RTEL1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: RTEL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RTEL1 were set to 39156922
Phenotypes for gene: RTEL1 were set to Familial Progressive Myoclonus Epilepsy
Review for gene: RTEL1 was set to RED
Added comment: PMID: 39156922 reports two sibling from a consanguineous family who had familial progressive myoclonus epilepsy. Both of the sibling were homozygous for a KCNH8 variant (NM_144633.3:c.298T>C; p.Tyr100His) and a RTEL1 variant (NM_032957.5:c.691G>T; p.Asp231Tyr).
Sources: Literature
Early onset or syndromic epilepsy v7.75 KCNH8 Sarah Leigh gene: KCNH8 was added
gene: KCNH8 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: KCNH8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCNH8 were set to 39156922
Phenotypes for gene: KCNH8 were set to Familial Progressive Myoclonus Epilepsy
Review for gene: KCNH8 was set to RED
Added comment: PMID: 39156922 reports two sibling from a consanguineous family who had familial progressive myoclonus epilepsy. Both of the sibling were homozygous for a KCNH8 variant (NM_144633.3:c.298T>C; p.Tyr100His) and a RTEL1 variant (NM_032957.5:c.691G>T; p.Asp231Tyr).
Sources: Literature
Skeletal dysplasia v7.36 VPS33A Sarah Leigh Added comment: Comment on publications: PMID: 39273517 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Skeletal dysplasia v7.36 VPS33A Sarah Leigh Publications for gene: VPS33A were set to 27547915; 28013294; 31070736; 39273517
Intellectual disability v8.196 VPS33A Sarah Leigh Added comment: Comment on publications: PMID: 39273517 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.196 VPS33A Sarah Leigh Publications for gene: VPS33A were set to 27547915; 28013294; 31070736; 39273517
Intellectual disability v8.195 VPS33A Sarah Leigh Classified gene: VPS33A as Amber List (moderate evidence)
Intellectual disability v8.195 VPS33A Sarah Leigh Gene: vps33a has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v7.35 VPS33A Sarah Leigh Classified gene: VPS33A as Amber List (moderate evidence)
Skeletal dysplasia v7.35 VPS33A Sarah Leigh Gene: vps33a has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v7.34 VPS33A Sarah Leigh gene: VPS33A was added
gene: VPS33A was added to Skeletal dysplasia. Sources: Literature
Q1_25_ promote_green tags were added to gene: VPS33A.
Mode of inheritance for gene: VPS33A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS33A were set to 27547915; 28013294; 31070736; 39273517
Phenotypes for gene: VPS33A were set to Mucopolysaccharidosis-plus syndrome, OMIM:617303; mucopolysaccharidosis-plus syndrome, MONDO:0015012
Review for gene: VPS33A was set to GREEN
Added comment: There are numerous reports of the homozygous VPS33A variant: NM 022916.5: c.1492C > T, p.Arg498Trp in cases of Mucopolysaccharidosis-plus syndrome (OMIM:617303)(PMID: 27547915;28013294;31070736;39273517). Common features of this syndrome include: hepatomegaly, splenomegaly, respiratory difficulties, developmental delay including limited cognitive abilities and various skeletal issues (PMID: 27547915;28013294;31070736;39273517).
Sources: Literature
Intellectual disability v8.194 VPS33A Sarah Leigh gene: VPS33A was added
gene: VPS33A was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: VPS33A.
Mode of inheritance for gene: VPS33A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS33A were set to 27547915; 28013294; 31070736; 39273517
Phenotypes for gene: VPS33A were set to Mucopolysaccharidosis-plus syndrome, OMIM:617303; mucopolysaccharidosis-plus syndrome, MONDO:0015012
Review for gene: VPS33A was set to GREEN
Added comment: There are numerous reports of the homozygous VPS33A variant: NM 022916.5: c.1492C > T, p.Arg498Trp in cases of Mucopolysaccharidosis-plus syndrome (OMIM:617303)(PMID: 27547915;28013294;31070736;39273517). Common features of this syndrome include: hepatomegaly, splenomegaly, respiratory difficulties, developmental delay including limited cognitive abilities and various skeletal issues (PMID: 27547915;28013294;31070736;39273517).
Sources: Literature
Intellectual disability v8.193 CRMP1 Achchuthan Shanmugasundram Classified gene: CRMP1 as Amber List (moderate evidence)
Intellectual disability v8.193 CRMP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported with moderate intellectual disability and with monoallelic CRMP1 variants. However, one patient with a different monoallelic CRMP1 variant had normal IQ. Hence, this gene should be rated amber with current evidence.

The 'watchlist' tag has been added to review this gene in light of any new evidence in the future.
Intellectual disability v8.193 CRMP1 Achchuthan Shanmugasundram Gene: crmp1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.192 CRMP1 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: CRMP1.
Intellectual disability v8.192 CRMP1 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39758889 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.192 CRMP1 Achchuthan Shanmugasundram Publications for gene: CRMP1 were set to 36511780; 39758889
Intellectual disability v8.191 CRMP1 Achchuthan Shanmugasundram gene: CRMP1 was added
gene: CRMP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CRMP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRMP1 were set to 36511780; 39758889
Phenotypes for gene: CRMP1 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: CRMP1 was set to AMBER
Added comment: PMID:36511780 reported the identification of three different heterozygous de novo variants in the CRMP1 gene (p.(Pro589Leu), p.(Thr427Met) & p.(Phe351Ser)) in three unrelated individuals with a neurodevelopmental disorder presenting with muscular hypotonia, intellectual disability, and/or autism spectrum disorder. ID was moderate in two of them, while IQ was normal in one. There is also functional evidence available for these variants.

PMID:39758889 reported the identification of a novel heterozygous de novo frameshift variant in CRMP1 (p.(Lys586fs)) in a 9-year-old male patient presenting with phenotypes such as autism, language delay, hyperactivity, and learning disabilities. This patient was reported with moderate ID.
Sources: Literature
Monogenic short stature v1.13 GAP43 Achchuthan Shanmugasundram changed review comment from: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (4 involving deletion of a region including GAP43, one duplication and one SNV). Only one of these cases with region deletion had moderate ID, while two others had mild ID.
Sources: Literature; to: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (3 involving deletion of a region including GAP43, two siblings with duplication and one SNV). Only one of the siblings with region duplication had moderate ID, while the other sibling and another patient with region deletion had mild ID.

This gene has not yet been associated with phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Monogenic short stature v1.13 GAP43 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39738362 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Monogenic short stature v1.13 GAP43 Achchuthan Shanmugasundram Publications for gene: GAP43 were set to 39738362
Intellectual disability v8.190 GAP43 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39738362 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.190 GAP43 Achchuthan Shanmugasundram Publications for gene: GAP43 were set to 39738362
Intellectual disability v8.189 GAP43 Achchuthan Shanmugasundram changed review comment from: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (3 involving deletion of a region including GAP43, two siblings with duplication and one SNV). Only one of the siblings with region duplication had moderate ID, while the other sibling and another patient with region deletion had mild ID.
Sources: Literature; to: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (3 involving deletion of a region including GAP43, two siblings with duplication and one SNV). Only one of the siblings with region duplication had moderate ID, while the other sibling and another patient with region deletion had mild ID.

This gene has not yet been associated with phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.189 ERCC4 Sarah Leigh Added comment: Comment on publications: PMID: 39769235 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.189 ERCC4 Sarah Leigh Publications for gene: ERCC4 were set to 39769235
Intellectual disability v8.188 GAP43 Achchuthan Shanmugasundram changed review comment from: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (4 involving deletion of a region including GAP43, one duplication and one SNV). Only one of these cases with region deletion had moderate ID, while two others had mild ID.
Sources: Literature; to: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (3 involving deletion of a region including GAP43, two siblings with duplication and one SNV). Only one of the siblings with region duplication had moderate ID, while the other sibling and another patient with region deletion had mild ID.
Sources: Literature
Structural eye disease v4.4 TOMM7 Sarah Leigh Added comment: Comment on publications: PMID: 39615461 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Structural eye disease v4.4 TOMM7 Sarah Leigh Publications for gene: TOMM7 were set to 39615461
Structural eye disease v4.3 TOMM7 Sarah Leigh Classified gene: TOMM7 as Amber List (moderate evidence)
Structural eye disease v4.3 TOMM7 Sarah Leigh Gene: tomm7 has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.12 GAP43 Achchuthan Shanmugasundram gene: GAP43 was added
gene: GAP43 was added to Monogenic short stature. Sources: Literature
Mode of inheritance for gene: GAP43 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GAP43 were set to 39738362
Phenotypes for gene: GAP43 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: GAP43 was set to RED
Added comment: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (4 involving deletion of a region including GAP43, one duplication and one SNV). Only one of these cases with region deletion had moderate ID, while two others had mild ID.
Sources: Literature
Intellectual disability v8.188 GAP43 Achchuthan Shanmugasundram gene: GAP43 was added
gene: GAP43 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GAP43 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GAP43 were set to 39738362
Phenotypes for gene: GAP43 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: GAP43 was set to RED
Added comment: PMID:39738362 reported the identification of a heterozygous missense variant in the GAP43 gene (p.(Glu146Lys)) in a 15-year-old female patient with moderate intellectual disability, neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities.

The variant GAP43 protein was found to be unstable in neuronal cells and the disruption of Gap43 in mouse embryonic cortical neurons impaired axonal elongation and dendrite formation.

There were six previous cases reported with GAP43 abnormalities (4 involving deletion of a region including GAP43, one duplication and one SNV). Only one of these cases with region deletion had moderate ID, while two others had mild ID.
Sources: Literature
Intellectual disability v8.187 HINT1 Sarah Leigh Added comment: Comment on publications: PMID: 39596683 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.187 HINT1 Sarah Leigh Publications for gene: HINT1 were set to 22961002; 34694653; 39596683
Skeletal dysplasia v7.33 LRRC8C Achchuthan Shanmugasundram Classified gene: LRRC8C as Amber List (moderate evidence)
Skeletal dysplasia v7.33 LRRC8C Achchuthan Shanmugasundram Gene: lrrc8c has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v7.32 LRRC8C Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39623139 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Skeletal dysplasia v7.32 LRRC8C Achchuthan Shanmugasundram Publications for gene: LRRC8C were set to 39623139
Severe microcephaly v7.22 LRRC8C Achchuthan Shanmugasundram Classified gene: LRRC8C as Amber List (moderate evidence)
Severe microcephaly v7.22 LRRC8C Achchuthan Shanmugasundram Gene: lrrc8c has been classified as Amber List (Moderate Evidence).
Severe microcephaly v7.21 LRRC8C Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39623139 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Severe microcephaly v7.21 LRRC8C Achchuthan Shanmugasundram Publications for gene: LRRC8C were set to 39623139
Optic neuropathy v4.43 LRRC8C Achchuthan Shanmugasundram Classified gene: LRRC8C as Amber List (moderate evidence)
Optic neuropathy v4.43 LRRC8C Achchuthan Shanmugasundram Gene: lrrc8c has been classified as Amber List (Moderate Evidence).
Optic neuropathy v4.42 LRRC8C Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39623139 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Optic neuropathy v4.42 LRRC8C Achchuthan Shanmugasundram Publications for gene: LRRC8C were set to 39623139
Monogenic short stature v1.11 LRRC8C Achchuthan Shanmugasundram Classified gene: LRRC8C as Amber List (moderate evidence)
Monogenic short stature v1.11 LRRC8C Achchuthan Shanmugasundram Gene: lrrc8c has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.10 LRRC8C Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39623139 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Monogenic short stature v1.10 LRRC8C Achchuthan Shanmugasundram Publications for gene: LRRC8C were set to 39623139
Intellectual disability v8.186 LRRC8C Achchuthan Shanmugasundram changed review comment from: Comment on publications: PMID:39623139 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques; to: Comment on publications: PMID:39623139 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.186 LRRC8C Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39623139 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v8.186 LRRC8C Achchuthan Shanmugasundram Publications for gene: LRRC8C were set to 39623139
Intellectual disability v8.185 LRRC8C Achchuthan Shanmugasundram Classified gene: LRRC8C as Amber List (moderate evidence)
Intellectual disability v8.185 LRRC8C Achchuthan Shanmugasundram Gene: lrrc8c has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.9 LRRC8C Achchuthan Shanmugasundram gene: LRRC8C was added
gene: LRRC8C was added to Monogenic short stature. Sources: Literature
Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRRC8C were set to 39623139
Phenotypes for gene: LRRC8C were set to TIMES syndrome, OMIM:621056
Mode of pathogenicity for gene: LRRC8C was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LRRC8C was set to AMBER
Added comment: PMID:39623139 reported two unrelated individuals with a multisystem disorder characterised by considerable phenotypic variability, but with overlapping features including telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature.

One patient had a 1-bp heterozygous insertion (p.(Leu400IlefsTer8)) in LRRC8C gene, while the other one had a heterozygous missense variant in the same gene (p.(Val390Leu)). There is also evidence from in vitro functional assay available. The evidence also suggests that both variants result in gain-of-function effect.

`This gene has been associated with relevant phenotype in OMIM (MIM #621056), but not yet in Gene2Phenotype.
Sources: Literature
Optic neuropathy v4.41 LRRC8C Achchuthan Shanmugasundram gene: LRRC8C was added
gene: LRRC8C was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRRC8C were set to 39623139
Phenotypes for gene: LRRC8C were set to TIMES syndrome, OMIM:621056
Mode of pathogenicity for gene: LRRC8C was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LRRC8C was set to AMBER
Added comment: PMID:39623139 reported two unrelated individuals with a multisystem disorder characterised by considerable phenotypic variability, but with overlapping features including telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature.

One patient had a 1-bp heterozygous insertion (p.(Leu400IlefsTer8)) in LRRC8C gene, while the other one had a heterozygous missense variant in the same gene (p.(Val390Leu)). There is also evidence from in vitro functional assay available. The evidence also suggests that both variants result in gain-of-function effect.

`This gene has been associated with relevant phenotype in OMIM (MIM #621056), but not yet in Gene2Phenotype.
Sources: Literature
Severe microcephaly v7.20 LRRC8C Achchuthan Shanmugasundram gene: LRRC8C was added
gene: LRRC8C was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRRC8C were set to 39623139
Phenotypes for gene: LRRC8C were set to TIMES syndrome, OMIM:621056
Mode of pathogenicity for gene: LRRC8C was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LRRC8C was set to AMBER
Added comment: PMID:39623139 reported two unrelated individuals with a multisystem disorder characterised by considerable phenotypic variability, but with overlapping features including telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature.

One patient had a 1-bp heterozygous insertion (p.(Leu400IlefsTer8)) in LRRC8C gene, while the other one had a heterozygous missense variant in the same gene (p.(Val390Leu)). There is also evidence from in vitro functional assay available. The evidence also suggests that both variants result in gain-of-function effect.

`This gene has been associated with relevant phenotype in OMIM (MIM #621056), but not yet in Gene2Phenotype.
Sources: Literature
Skeletal dysplasia v7.31 LRRC8C Achchuthan Shanmugasundram gene: LRRC8C was added
gene: LRRC8C was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRRC8C were set to 39623139
Phenotypes for gene: LRRC8C were set to TIMES syndrome, OMIM:621056
Mode of pathogenicity for gene: LRRC8C was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LRRC8C was set to AMBER
Added comment: PMID:39623139 reported two unrelated individuals with a multisystem disorder characterised by considerable phenotypic variability, but with overlapping features including telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature.

One patient had a 1-bp heterozygous insertion (p.(Leu400IlefsTer8)) in LRRC8C gene, while the other one had a heterozygous missense variant in the same gene (p.(Val390Leu)). There is also evidence from in vitro functional assay available. The evidence also suggests that both variants result in gain-of-function effect.

`This gene has been associated with relevant phenotype in OMIM (MIM #621056), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.184 LRRC8C Achchuthan Shanmugasundram gene: LRRC8C was added
gene: LRRC8C was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRRC8C were set to 39623139
Phenotypes for gene: LRRC8C were set to TIMES syndrome, OMIM:621056
Mode of pathogenicity for gene: LRRC8C was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LRRC8C was set to AMBER
Added comment: PMID:39623139 reported two unrelated individuals with a multisystem disorder characterised by considerable phenotypic variability, but with overlapping features including telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature.

One patient had a 1-bp heterozygous insertion (p.(Leu400IlefsTer8)) in LRRC8C gene, while the other one had a heterozygous missense variant in the same gene (p.(Val390Leu)). There is also evidence from in vitro functional assay available. The evidence also suggests that both variants result in gain-of-function effect.

`This gene has been associated with relevant phenotype in OMIM (MIM #621056), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.183 WFS1 Achchuthan Shanmugasundram changed review comment from: PMID:39767643 reported the identification of an ultra-rare, mono-allelic missense variant in the WFS1 gene (p. Asp711Asn) in a nine-year-old girl that showed phenotypic manifestations of intellectual impairment, microcephaly, and epilepsy. There was a positive family history in previous generations for cognitive impairment.; to: PMID:39767643 reported the identification of an ultra-rare, mono-allelic missense variant in the WFS1 gene (p. Asp711Asn) in a nine-year-old girl that showed phenotypic manifestations of intellectual impairment, microcephaly, and epilepsy. There was a positive family history in previous generations for cognitive impairment.

Although there are multiple phenotypes available for this gene in OMIM, mental retardation/ cognitive impairment has been recorded as a clinical manifestation seen in some patients with the autosomal recessive Wolfram syndrome 1 (MIM #222300). However, ID has not been associated with any autosomal dominant syndromes. In addition, ID forms part of a broader phenotype.

Hence, this gene can only be rated red for both monoallelic and biallelic disease associations in this panel.
Intellectual disability v8.183 WFS1 Achchuthan Shanmugasundram edited their review of gene: WFS1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v8.183 WFS1 Achchuthan Shanmugasundram edited their review of gene: WFS1: Changed rating: RED
Intellectual disability v8.183 WFS1 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39767643 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.183 WFS1 Achchuthan Shanmugasundram Publications for gene: WFS1 were set to
Intellectual disability v8.182 WFS1 Achchuthan Shanmugasundram reviewed gene: WFS1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39767643; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.182 LMNA Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39767643 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.182 LMNA Achchuthan Shanmugasundram Publications for gene: LMNA were set to 25529582; 39767643
Intellectual disability v8.181 LMNA Achchuthan Shanmugasundram Classified gene: LMNA as Amber List (moderate evidence)
Intellectual disability v8.181 LMNA Achchuthan Shanmugasundram Gene: lmna has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.180 LMNA Achchuthan Shanmugasundram changed review comment from: PMID:39767643 reported the identification of a heterozygous missense variant in LMNA gene (p. Glu443Gly) in a 16-year-old boy affected with intellectual impairment, cardiac manifestation, diabetes mellitus, a cataract in the right eye, epilepsy, and skin atrophy on his back. This family showed no positive history of neurodevelopmental disorders (NDDs) in the five previous generations, while one sibling was affected by a NDD phenotype.

There are four cases reported in the Decipher database with sequence variants in LMNA gene (https://www.deciphergenomics.org/gene/LMNA/patient-overlap/snvs), of which the patient with frameshift variant (p.Glu223AspfsTer7) was reported with a number of phenotypes including global developmental delay.; to: PMID:39767643 reported the identification of a heterozygous missense variant in LMNA gene (p. Glu443Gly) in a 16-year-old boy affected with intellectual impairment, cardiac manifestation, diabetes mellitus, a cataract in the right eye, epilepsy, and skin atrophy on his back. This family showed no positive history of neurodevelopmental disorders (NDDs) in the five previous generations, while one sibling was affected by a NDD phenotype.

There are four cases reported in the Decipher database with sequence variants in LMNA gene (https://www.deciphergenomics.org/gene/LMNA/patient-overlap/snvs), of which the patient with frameshift variant (p.Glu223AspfsTer7) was reported with a number of phenotypes including global developmental delay. This variant is annotated to be likely pathogenic and with the contribution of the variant to phenotype is uncertain.
Intellectual disability v8.180 LMNA Achchuthan Shanmugasundram Publications for gene: LMNA were set to
Intellectual disability v8.179 LMNA Achchuthan Shanmugasundram Mode of inheritance for gene: LMNA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.178 LMNA Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v8.178 LMNA Achchuthan Shanmugasundram commented on gene: LMNA: PMID:39767643 reported the identification of a heterozygous missense variant in LMNA gene (p. Glu443Gly) in a 16-year-old boy affected with intellectual impairment, cardiac manifestation, diabetes mellitus, a cataract in the right eye, epilepsy, and skin atrophy on his back. This family showed no positive history of neurodevelopmental disorders (NDDs) in the five previous generations, while one sibling was affected by a NDD phenotype.

There are four cases reported in the Decipher database with sequence variants in LMNA gene (https://www.deciphergenomics.org/gene/LMNA/patient-overlap/snvs), of which the patient with frameshift variant (p.Glu223AspfsTer7) was reported with a number of phenotypes including global developmental delay.
Intellectual disability v8.178 LMNA Achchuthan Shanmugasundram reviewed gene: LMNA: Rating: AMBER; Mode of pathogenicity: None; Publications: 25529582, 39767643; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.178 ERCC4 Sarah Leigh reviewed gene: ERCC4: Rating: RED; Mode of pathogenicity: None; Publications: 39769235; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.178 ERCC4 Sarah Leigh Publications for gene: ERCC4 were set to
Intellectual disability v8.178 ERCC4 Sarah Leigh Phenotypes for gene: ERCC4 were changed from Xeroderma pigmentosum, group F, 278760; XFE progeroid syndrome, 610965; Fanconi anemia, complementation group Q, 615272; Xeroderma pigmentosum, type F/Cockayne syndrome, 278760 to Xeroderma pigmentosum, group F 278760; XFE progeroid syndrome, OMIM: 610965
Structural eye disease v4.2 TOMM7 Sarah Leigh gene: TOMM7 was added
gene: TOMM7 was added to Structural eye disease. Sources: Literature
Q1_25_ promote_green tags were added to gene: TOMM7.
Mode of inheritance for gene: TOMM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOMM7 were set to 39615461
Phenotypes for gene: TOMM7 were set to Garg-Mishra progeroid syndrome, OMIM:620601
Review for gene: TOMM7 was set to GREEN
Added comment: Ocular features are reported in nine members of seven unrelated Chinese families, who all are homozygous for the same TOMM7 variant ( NM_019059.5:c.86C>T; NP_061932.1:p.P29L)(PMID: 39615461). The common features were Maculopathy (7/9 individuals), Amblyobia (6/9 individuals) and hyperopia (6/9 individuals).
Sources: Literature
Intellectual disability v8.177 HINT1 Sarah Leigh reviewed gene: HINT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuromyotonia and axonal neuropathy, autosomal recessive, OMIM:137200, Gamstorp-Wohlfart syndrome, MONDO:0007646; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.177 HINT1 Sarah Leigh Publications for gene: HINT1 were set to 22961002; 34694653; 39596683
Intellectual disability v8.176 HINT1 Sarah Leigh Phenotypes for gene: HINT1 were changed from Neuromyotonia and axonal neuropathy, autosomal recessive, 137200 to Neuromyotonia and axonal neuropathy, autosomal recessive, OMIM:137200; Gamstorp-Wohlfart syndrome, MONDO:0007646
Intellectual disability v8.175 HINT1 Sarah Leigh Publications for gene: HINT1 were set to
Distal myopathies v6.3 TIA1 Cassandra Smith reviewed gene: TIA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Deafness and congenital structural abnormalities v1.30 DAP3 Achchuthan Shanmugasundram changed review comment from: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101).; to: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101), but not yet in Gene2Phenotype.
Monogenic hearing loss v4.82 DAP3 Achchuthan Shanmugasundram changed review comment from: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101).
Sources: Literature; to: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.174 DAP3 Achchuthan Shanmugasundram changed review comment from: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101).
Sources: Literature; to: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.174 PLAT Achchuthan Shanmugasundram changed review comment from: PMID:39574431 reported the identification of three different homozygous truncating variants in PLAT gene in four individuals from three unrelated families. All of them presented with tetraventricular hydrocephalus. Dandy–Walker malformation was reported in three unrelated cases, of which mild intellectual disability was reported in one (family 2). Global developmental delay was reported in another (family 3), but this could partially be explained by a co-occurring Cohen syndrome diagnosis. Mild ID was also reported in the proband from family 1 that did not show Dandy–Walker malformation.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39574431 reported the identification of three different homozygous truncating variants in PLAT gene in four cases from three unrelated families. All of them presented with tetraventricular hydrocephalus. Dandy–Walker malformation was reported in three unrelated cases (two individuals and one foetus), of which mild intellectual disability was reported in one (family 2). Global developmental delay was reported in another (family 3), but this could partially be explained by a co-occurring Cohen syndrome diagnosis. Mild ID was also reported in the proband from family 1 that did not show Dandy–Walker malformation.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.174 PLAT Achchuthan Shanmugasundram changed review comment from: PMID:39574431 reported the identification of three different homozygous truncating variants in PLAT gene in four individuals from three unrelated families. All of them presented with tetraventricular hydrocephalus. Dandy–Walker malformation was reported in three unrelated cases, of which mild intellectual disability was reported in two. Global developmental delay was reported in the third one.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39574431 reported the identification of three different homozygous truncating variants in PLAT gene in four individuals from three unrelated families. All of them presented with tetraventricular hydrocephalus. Dandy–Walker malformation was reported in three unrelated cases, of which mild intellectual disability was reported in one (family 2). Global developmental delay was reported in another (family 3), but this could partially be explained by a co-occurring Cohen syndrome diagnosis. Mild ID was also reported in the proband from family 1 that did not show Dandy–Walker malformation.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.174 DAP3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene is currently rated amber as there is only case identified with severe ID, while two other cases had only mild ID.; to: Comment on list classification: This gene is currently rated amber as there is only one case identified with severe ID, while two other cases had only mild ID.
Intellectual disability v8.174 PLAT Achchuthan Shanmugasundram Classified gene: PLAT as Amber List (moderate evidence)
Intellectual disability v8.174 PLAT Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated amber with current evidence as there is one case reported with GDD and two cases reported with only mild ID.
Intellectual disability v8.174 PLAT Achchuthan Shanmugasundram Gene: plat has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.173 DAP3 Achchuthan Shanmugasundram Classified gene: DAP3 as Amber List (moderate evidence)
Intellectual disability v8.173 DAP3 Achchuthan Shanmugasundram Gene: dap3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.172 DAP3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene is currently rated amber as there is only case identified with severe ID, while two other cases had only mild ID.; to: Comment on list classification: This gene is currently rated amber as there is only case identified with severe ID, while two other cases had only mild ID.
Intellectual disability v8.172 DAP3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene is currently rated red as there is only case identified with severe ID, while two other cases had only mild ID.; to: Comment on list classification: This gene is currently rated amber as there is only case identified with severe ID, while two other cases had only mild ID.
Intellectual disability v8.172 DAP3 Achchuthan Shanmugasundram edited their review of gene: DAP3: Changed rating: AMBER
Intellectual disability v8.172 PLAT Achchuthan Shanmugasundram gene: PLAT was added
gene: PLAT was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLAT were set to 39574431
Phenotypes for gene: PLAT were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: PLAT was set to AMBER
Added comment: PMID:39574431 reported the identification of three different homozygous truncating variants in PLAT gene in four individuals from three unrelated families. All of them presented with tetraventricular hydrocephalus. Dandy–Walker malformation was reported in three unrelated cases, of which mild intellectual disability was reported in two. Global developmental delay was reported in the third one.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v8.171 IARS2 Achchuthan Shanmugasundram Publications for gene: IARS2 were set to 25130867; 28328135; 39169373
Intellectual disability v8.170 IARS2 Achchuthan Shanmugasundram Phenotypes for gene: IARS2 were changed from Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, 616007 to Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, OMIM:616007
Intellectual disability v8.170 IARS2 Achchuthan Shanmugasundram Publications for gene: IARS2 were set to 25130867; 28328135
Intellectual disability v8.169 IARS2 Achchuthan Shanmugasundram reviewed gene: IARS2: Rating: RED; Mode of pathogenicity: None; Publications: 39169373; Phenotypes: Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, OMIM:616007; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.169 NHLRC2 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: NHLRC2.
Intellectual disability v8.169 DAP3 Achchuthan Shanmugasundram Classified gene: DAP3 as Red List (low evidence)
Intellectual disability v8.169 DAP3 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene is currently rated red as there is only case identified with severe ID, while two other cases had only mild ID.
Intellectual disability v8.169 DAP3 Achchuthan Shanmugasundram Gene: dap3 has been classified as Red List (Low Evidence).
Intellectual disability v8.168 DAP3 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39701103 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.168 DAP3 Achchuthan Shanmugasundram Publications for gene: DAP3 were set to 39701103
Intellectual disability v8.167 DAP3 Achchuthan Shanmugasundram gene: DAP3 was added
gene: DAP3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAP3 were set to 39701103
Phenotypes for gene: DAP3 were set to Perrault syndrome 7, OMIM:621101
Review for gene: DAP3 was set to RED
Added comment: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101).
Sources: Literature
Deafness and congenital structural abnormalities v1.30 DAP3 Achchuthan Shanmugasundram Classified gene: DAP3 as Green List (high evidence)
Deafness and congenital structural abnormalities v1.30 DAP3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (five unrelated cases and functional work) for the promotion of this gene to green rating on this panel.
Deafness and congenital structural abnormalities v1.30 DAP3 Achchuthan Shanmugasundram Gene: dap3 has been classified as Green List (High Evidence).
Deafness and congenital structural abnormalities v1.29 DAP3 Achchuthan Shanmugasundram Publications for gene: DAP3 were set to PMID:39701103
Deafness and congenital structural abnormalities v1.28 DAP3 Achchuthan Shanmugasundram Phenotypes for gene: DAP3 were changed from Sensorineural hearing loss; primary ovarian insufficiency; lactic acidosis; intellectual disability to Perrault syndrome 7, OMIM:621101
Deafness and congenital structural abnormalities v1.27 DAP3 Achchuthan Shanmugasundram reviewed gene: DAP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39701103; Phenotypes: Perrault syndrome 7, OMIM:621101; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v4.82 DAP3 Achchuthan Shanmugasundram Classified gene: DAP3 as Amber List (moderate evidence)
Monogenic hearing loss v4.82 DAP3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (five unrelated cases and functional work) for the association of this gene to hearing loss. Hence, this gene can be promoted to green rating in the next GMS update.
Monogenic hearing loss v4.82 DAP3 Achchuthan Shanmugasundram Gene: dap3 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v4.81 DAP3 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39701103 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Monogenic hearing loss v4.81 DAP3 Achchuthan Shanmugasundram Publications for gene: DAP3 were set to 39701103
Monogenic hearing loss v4.80 DAP3 Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: DAP3.
Monogenic hearing loss v4.80 DAP3 Achchuthan Shanmugasundram changed review comment from: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available for this gene.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101).
Sources: Literature; to: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101).
Sources: Literature
Monogenic hearing loss v4.80 DAP3 Achchuthan Shanmugasundram gene: DAP3 was added
gene: DAP3 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: DAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAP3 were set to 39701103
Phenotypes for gene: DAP3 were set to Perrault syndrome 7, OMIM:621101
Review for gene: DAP3 was set to GREEN
Added comment: PMID:39701103 reported the identification of biallelic variants in DAP3 gene in five unrelated individuals presenting with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. All five individuals had bilateral sensorineural hearing loss and the severity was profound in three of them, while not reported in the other two. Severe intellectual disability was reported in one individual and mild ID was reported in two individuals. There is also functional evidence available for this gene.

This gene has been associated with relevant phenotypes in OMIM (MIM #621101).
Sources: Literature
Intellectual disability v8.166 NHLRC2 Achchuthan Shanmugasundram Classified gene: NHLRC2 as Amber List (moderate evidence)
Intellectual disability v8.166 NHLRC2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>15 unrelated cases with moderate/ severe GDD/ ID) for the promotion of this gene to green rating in the next GMS update.
Intellectual disability v8.166 NHLRC2 Achchuthan Shanmugasundram Gene: nhlrc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.165 NHLRC2 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39328589 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.165 NHLRC2 Achchuthan Shanmugasundram Publications for gene: NHLRC2 were set to 37188825; 39328589
Intellectual disability v8.164 NHLRC2 Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: NHLRC2.
Intellectual disability v8.164 NHLRC2 Achchuthan Shanmugasundram gene: NHLRC2 was added
gene: NHLRC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NHLRC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NHLRC2 were set to 37188825; 39328589
Phenotypes for gene: NHLRC2 were set to FINCA syndrome, OMIM:618278
Review for gene: NHLRC2 was set to GREEN
Added comment: PMID:37188825 reported 15 patients ranging in age from 22 months to 19 years, from 12 unrelated families with an overlapping phenotype with FINCA syndrome (MIM #618278). They were identified with nine novel NHLRC2 variants via exome sequencing. All these patients presented with moderate to severe global developmental delay and variable disease progression. Seizures, truncal hypotonia and movement disorders were also frequently observed.

PMID:39328589 reported two siblings of Chinese decent with FINCA syndrome and they were identified with the same compound heterozygous variants in NHLRC2 gene. Both of them presented with developmental delay, of which the younger brother was evaluated with a development quotient (DQ) of 39 at four months of age (normal range >85), indicating moderate intellectual disability.

This gene has also been associated with relevant phenotype on the DD panel of Gene2Phenotype, with a definitive rating.
Sources: Literature
Intellectual disability v8.163 DDX39B Mike Spiller gene: DDX39B was added
gene: DDX39B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DDX39B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX39B were set to PMID: 39918047
Review for gene: DDX39B was set to GREEN
Added comment: PMID: 39918047 - report 4 de novo missense variants in individuals with phenotypes of ID ranging from mild to severe (2 severe, 1 mild, 1 severity not stated but phenotype of GDD).
Hypotonia, short stature and skeletal abnormalities are also observed frequently.
Variants absent from gnomad, affect highly conserved amino acids in constrained regions of DEAD/DEAH box helicase domain.

Splice variant causing inframe deletion also identified in fifth family (proband and mother), but significance of this unclear as neither has ID.

Supported by functional studies:
Transcriptome profiling shows significant increase in abberant splicing events, consistent with DDX39B role as splicing factor.
Drosophila experiments - overexpression of WT human gene is lethal, but flies overexpressing variants were healthy, suggesting these variants cause loss of / reduced protein function.

Overall good evidence for DEAD box helicase missenses causing an autosomal dominant syndromic ID disorder.
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v3.25 CFAP54 Steven Cowman reviewed gene: CFAP54: Rating: GREEN; Mode of pathogenicity: None; Publications: 39362668, 37725231; Phenotypes: Primary ciliary dyskinesia, bronchiectasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.163 AFF2_GCC Sarah Leigh STR: AFF2_GCC was added
STR: AFF2_GCC was added to Intellectual disability. Sources: Literature
STR, NGS Not Validated tags were added to STR: AFF2_GCC.
Mode of inheritance for STR: AFF2_GCC was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for STR: AFF2_GCC were set to 8334699; 8023854; 21739600; 9299237; 11171404; 11923441; 19136466; 2356291
Phenotypes for STR: AFF2_GCC were set to Intellectual developmental disorder, X-linked 109, OMIM:309548; FRAXE intellectual disability, MONDO:0010659
Review for STR: AFF2_GCC was set to GREEN
Added comment: AFF2 transcribed from the forwards strand, which means that the repeated sequence is the forward strand sequence.

AFF2_GCC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

AFF2_GCC is on https://stripy.org/database

AFF2_GCC is on DRAGON 4.02.

The coordinates and pathogenic ranges of the sequence repeats were obtained from
https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3 and DRAGON 4.02/

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
DDG2P v5.48 TNFRSF13B Ronnie Wright reviewed gene: TNFRSF13B: Rating: RED; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: Other
Skeletal dysplasia v7.30 XYLT1_GCC Sarah Leigh changed review comment from: XYLT1 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

XYLT1_GCC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

XYLT1_GCC is on https://stripy.org/database

XYLT1_GCC is on DRAGON 4.02.

The coordinates and pathogenic ranges of the sequence repeats were obtained from
https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3 and were the same on https://stripy.org/database/ and DRAGON 4.02/

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature; to: XYLT1 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

XYLT1_GCC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

XYLT1_GCC is on https://stripy.org/database

XYLT1_GCC is on DRAGON 4.02.

The coordinates and pathogenic ranges of the sequence repeats were obtained from
https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3 and were the same on https://stripy.org/database/ and DRAGON 4.02/

There is enough evidence for XYLT1_GGC to be green on this panel. At least ten patients from at least eight families have either homozygous or compound heterozygous (with other XYLT1 variants) XYLT1_GGC expansions (PMID: 22711505;30554721).

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Skeletal dysplasia v7.30 XYLT1_GCC Sarah Leigh STR: XYLT1_GCC was added
STR: XYLT1_GCC was added to Skeletal dysplasia. Sources: Literature
STR, NGS Not Validated tags were added to STR: XYLT1_GCC.
Mode of inheritance for STR: XYLT1_GCC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: XYLT1_GCC were set to 22711505; 30554721
Phenotypes for STR: XYLT1_GCC were set to Desbuquois dysplasia 2, OMIM:615777; Desbuquois dysplasia 2, MONDO:0014343
Review for STR: XYLT1_GCC was set to GREEN
Added comment: XYLT1 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

XYLT1_GCC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

XYLT1_GCC is on https://stripy.org/database

XYLT1_GCC is on DRAGON 4.02.

The coordinates and pathogenic ranges of the sequence repeats were obtained from
https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3 and were the same on https://stripy.org/database/ and DRAGON 4.02/

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v7.23 THAP11_CAG Sarah Leigh commented on STR: THAP11_CAG: PMID: 37148549 - 2 Chinese cases but one case had unaffected father with same number of repeats, PMID: 38113319 - 1 European case but inconclusive due to additional STR.

Also PMID: 38757579 and PMID: 39441143 report no cases with this repeat.
Intellectual disability v8.162 THAP11_CAG Sarah Leigh commented on STR: THAP11_CAG: PMID: 37148549 - 2 Chinese cases but one case had unaffected father with same number of repeats, PMID: 38113319 - 1 European case but inconclusive due to additional STR.

Also PMID: 38757579 and PMID: 39441143 report no cases with this repeat.
Intellectual disability v8.162 THAP11_CAG Sarah Leigh Classified STR: THAP11_CAG as Red List (low evidence)
Intellectual disability v8.162 THAP11_CAG Sarah Leigh Added comment: Comment on list classification: This STR has not been approved by NHS STR working group and is not NGS Not Validated
Intellectual disability v8.162 THAP11_CAG Sarah Leigh Str: thap11_cag has been classified as Red List (Low Evidence).
Ataxia and cerebellar anomalies - narrow panel v7.23 THAP11_CAG Sarah Leigh Classified STR: THAP11_CAG as Red List (low evidence)
Ataxia and cerebellar anomalies - narrow panel v7.23 THAP11_CAG Sarah Leigh Added comment: Comment on list classification: This STR has not been approved by NHS STR working group and is not NGS Not Validated
Ataxia and cerebellar anomalies - narrow panel v7.23 THAP11_CAG Sarah Leigh Str: thap11_cag has been classified as Red List (Low Evidence).
Intellectual disability v8.161 THAP11_CAG Sarah Leigh STR: THAP11_CAG was added
STR: THAP11_CAG was added to Intellectual disability. Sources: Literature
STR, NGS Not Validated tags were added to STR: THAP11_CAG.
Mode of inheritance for STR: THAP11_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: THAP11_CAG were set to 37148549; 38757579; 39441143
Phenotypes for STR: THAP11_CAG were set to Spinocerebellar ataxia 51, OMIM:620947
Review for STR: THAP11_CAG was set to RED
Added comment: THAP11 transcribed from the forward strand.
THAP11_CAG is not on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3
THAP11_CAG is not is not DRAGON 4.02 or other previous versions.
The coordinates and pathogenic ranges of the sequence repeats were obtained from https://stripy.org/database/THAP11

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v7.22 THAP11_CAG Sarah Leigh STR: THAP11_CAG was added
STR: THAP11_CAG was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
STR, NGS Not Validated tags were added to STR: THAP11_CAG.
Mode of inheritance for STR: THAP11_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: THAP11_CAG were set to 37148549; 38757579; 39441143
Phenotypes for STR: THAP11_CAG were set to Spinocerebellar ataxia 51, OMIM:620947
Review for STR: THAP11_CAG was set to RED
Added comment: THAP11 transcribed from the forward strand.
THAP11_CAG is not on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3
THAP11_CAG is not is not DRAGON 4.02 or other previous versions.
The coordinates and pathogenic ranges of the sequence repeats were obtained from https://stripy.org/database/THAP11.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Intellectual disability v8.160 PPP2R2B Sarah Leigh Mode of pathogenicity for gene: PPP2R2B was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Intellectual disability v8.159 PPP2R2B Sarah Leigh Classified gene: PPP2R2B as Amber List (moderate evidence)
Intellectual disability v8.159 PPP2R2B Sarah Leigh Gene: ppp2r2b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.74 PPP2R2B Sarah Leigh Classified gene: PPP2R2B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.74 PPP2R2B Sarah Leigh Gene: ppp2r2b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.73 PPP2R2B Sarah Leigh Added comment: Comment on publications: PMID: 39565297 and 25356899 were identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.73 PPP2R2B Sarah Leigh Publications for gene: PPP2R2B were set to 39565297; 25356899
Early onset or syndromic epilepsy v7.72 PPP2R2B Sarah Leigh Added comment: Comment on phenotypes: The PPP2R2B_CAG variant is associated with Spinocerebellar ataxia 12, OMIM:604326
Early onset or syndromic epilepsy v7.72 PPP2R2B Sarah Leigh Phenotypes for gene: PPP2R2B were changed from neurodevelopmental syndrome to neurodevelopmental syndrome
Early onset or syndromic epilepsy v7.71 PPP2R2B Sarah Leigh gene: PPP2R2B was added
gene: PPP2R2B was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_25_ promote_green tags were added to gene: PPP2R2B.
Mode of inheritance for gene: PPP2R2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP2R2B were set to 39565297; 25356899
Phenotypes for gene: PPP2R2B were set to neurodevelopmental syndrome
Review for gene: PPP2R2B was set to GREEN
Added comment: Sources: Literature
Intellectual disability v8.158 PPP2R2B Sarah Leigh Added comment: Comment on phenotypes: The PPP2R2B_CAG variant is associated with Spinocerebellar ataxia 12, OMIM:604326
Intellectual disability v8.158 PPP2R2B Sarah Leigh Phenotypes for gene: PPP2R2B were changed from Spinocerebellar ataxia 12, OMIM:604326 to neurodevelopmental syndrome
Intellectual disability v8.157 PPP2R2B Sarah Leigh Added comment: Comment on publications: PMID: 39565297 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.157 PPP2R2B Sarah Leigh Publications for gene: PPP2R2B were set to 25356899
Intellectual disability v8.156 PPP2R2B Sarah Leigh edited their review of gene: PPP2R2B: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.156 PPP2R2B Sarah Leigh Tag nucleotide-repeat-expansion was removed from gene: PPP2R2B.
Tag currently-ngs-unreportable was removed from gene: PPP2R2B.
Tag Q1_25_ promote_green tag was added to gene: PPP2R2B.
Intellectual disability v8.156 PPP2R2B Sarah Leigh reviewed gene: PPP2R2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 39565297, 25356899; Phenotypes: neurodevelopmental syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v8.156 PPP2R2B_CAG Sarah Leigh reviewed STR: PPP2R2B_CAG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v3.25 CFAP46 Steven Cowman reviewed gene: CFAP46: Rating: AMBER; Mode of pathogenicity: None; Publications: 39362668; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v3.25 CFAP221 Steven Cowman reviewed gene: CFAP221: Rating: AMBER; Mode of pathogenicity: None; Publications: 31636325, 39362668; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital hypothyroidism v2.23 STRTS Sarah Leigh changed review comment from: This is an intergenic STR. The STR can be seen using the coordinates 15:88569434-88569449 http://may2024.archive.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000144218;r=15:88569412-88569475; to: This is an intergenic STR. The STR can be seen using the coordinates 15:88569434-88569449 http://may2024.archive.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000144218;r=15:88569412-88569475

The pathogenic variant of this STR is NOT an expansion, it is a reduction: normal is 4 repeats and disease is 3 repeats or a base change in one of the 4 repeats.
Adult onset leukodystrophy v5.4 CST3 David Lynch reviewed gene: CST3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38489591, PMID: 38729262; Phenotypes: leukodystrophy without amyloid angiopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v7.70 RYR3 Sarah Leigh Added comment: Comment on publications: PMID: 39220738 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.70 RYR3 Sarah Leigh Publications for gene: RYR3 were set to 25262651; 29667327; 29498452; 31230720; 39220738; 39840699
Early onset or syndromic epilepsy v7.69 RYR3 Sarah Leigh Phenotypes for gene: RYR3 were changed from Epileptic encephalopathy to idiopathic(non-lesional) partial epilepsy/susceptibility of seizures
Early onset or syndromic epilepsy v7.68 RYR3 Sarah Leigh edited their review of gene: RYR3: Changed phenotypes to: idiopathic(non-lesional) partial epilepsy/susceptibility of seizures
Early onset or syndromic epilepsy v7.68 RYR3 Sarah Leigh Classified gene: RYR3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.68 RYR3 Sarah Leigh Gene: ryr3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.67 RYR3 Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: RYR3.
Early onset or syndromic epilepsy v7.67 RYR3 Sarah Leigh edited their review of gene: RYR3: Added comment: Previously there have been four reports of seizures in patients with biallelic RYR3 variants (PMID: 25262651; 29667327; 39220738). Using a cohort of patients with idiopathic(non-lesional) partial epilepsy/susceptibility of seizures, authors of PMID: 39840699 report thirteen RYR3 variants in seven cases. In all but one of the cases, the variants are compound heterozygotes, with the remaining case having a de novo heterozygous RYR3 variant. Seizure onset was in childhood (1 to 7 years), brain MRIs were normal in all cases, there was no evidence of myopathy and there was a single case of intellectual disability (table 1, PMID: 39840699).; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.156 HMGXB4 Arina Puzriakova gene: HMGXB4 was added
gene: HMGXB4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HMGXB4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMGXB4 were set to 39166056
Phenotypes for gene: HMGXB4 were set to Intellectual disability, developmental delay, and dysmorphic features
Added comment: PMID: 39166056 (2024) report three affected individuals from a single family with ID/GDD, obesity and dysmorphic facial features. WGS revealed a homozygous frameshift variant (c.1193_1196del; p.(Lys398Argfs*25)) in exon 5 of the HMGXB4 gene which completely segregated with disease. RT-qPCR revealed a substantial decrease in the HMGXB4 gene expression in affected individuals as compared to unaffected individuals of the family.

Rating Red for now as only a single family has been identified to date.
Sources: Literature
Mitochondrial disorder with complex I deficiency v3.11 NDUFB7 Arina Puzriakova Tag watchlist was removed from gene: NDUFB7.
Tag Q1_25_ promote_green tag was added to gene: NDUFB7.
Possible mitochondrial disorder - nuclear genes v3.119 NDUFB7 Arina Puzriakova Classified gene: NDUFB7 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.119 NDUFB7 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Although only two unrelated cases have been reported to date (PMID: 33502047, 40025060) there is strong functional data and an animal model that support the association. The existence of a therapeutic strategy further supports timely inclusion of this gene on a diagnostic panel.
Possible mitochondrial disorder - nuclear genes v3.119 NDUFB7 Arina Puzriakova Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v7.16 NDUFB7 Arina Puzriakova Tag watchlist was removed from gene: NDUFB7.
Tag Q1_25_ promote_green tag was added to gene: NDUFB7.
Possible mitochondrial disorder - nuclear genes v3.118 NDUFB7 Arina Puzriakova Tag Q1_25_ promote_green tag was added to gene: NDUFB7.
Fetal anomalies v5.84 NDUFB7 Arina Puzriakova Tag Q1_25_ expert_review tag was added to gene: NDUFB7.
Fetal anomalies v5.84 NDUFB7 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Although only two unrelated cases have been reported to date (PMID: 33502047, 40025060) there is strong functional data and an animal model that support the association. The existence of a therapeutic strategy further supports timely inclusion of this gene on a diagnostic panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update but this will be flagged for expert review prior to inclusion.

Although only two unrelated cases have been reported to date (PMID: 33502047, 40025060) there is strong functional data and an animal model that support the association. The existence of a therapeutic strategy further supports timely inclusion of this gene on a diagnostic panel.
Likely inborn error of metabolism v7.16 NDUFB7 Arina Puzriakova Phenotypes for gene: NDUFB7 were changed from ?Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135 to Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135
Mitochondrial disorder with complex I deficiency v3.11 NDUFB7 Arina Puzriakova edited their review of gene: NDUFB7: Changed rating: GREEN; Changed publications to: 40025060; Changed phenotypes to: Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.118 NDUFB7 Arina Puzriakova edited their review of gene: NDUFB7: Changed publications to: 40025060; Changed phenotypes to: Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.84 NDUFB7 Arina Puzriakova edited their review of gene: NDUFB7: Changed publications to: 40025060; Changed phenotypes to: Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v3.11 NDUFB7 Arina Puzriakova Classified gene: NDUFB7 as Amber List (moderate evidence)
Mitochondrial disorder with complex I deficiency v3.11 NDUFB7 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Although only two unrelated cases have been reported to date (PMID: 33502047, 40025060) there is strong functional data and an animal model that support the association. The existence of a therapeutic strategy further supports timely inclusion of this gene on a diagnostic panel.
Mitochondrial disorder with complex I deficiency v3.11 NDUFB7 Arina Puzriakova Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.118 NDUFB7 Arina Puzriakova edited their review of gene: NDUFB7: Changed rating: GREEN
Fetal anomalies v5.84 NDUFB7 Arina Puzriakova edited their review of gene: NDUFB7: Changed rating: GREEN
Possible mitochondrial disorder - nuclear genes v3.118 NDUFB7 Arina Puzriakova Classified gene: NDUFB7 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.118 NDUFB7 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Although only two unrelated cases have been reported to date (PMID: 33502047, 40025060) there is strong functional data and an animal model that support the association. The existence of a therapeutic strategy further supports timely inclusion of this gene on a diagnostic panel.
Possible mitochondrial disorder - nuclear genes v3.118 NDUFB7 Arina Puzriakova Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v5.84 NDUFB7 Arina Puzriakova Classified gene: NDUFB7 as Amber List (moderate evidence)
Fetal anomalies v5.84 NDUFB7 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Although only two unrelated cases have been reported to date (PMID: 33502047, 40025060) there is strong functional data and an animal model that support the association. The existence of a therapeutic strategy further supports timely inclusion of this gene on a diagnostic panel.
Fetal anomalies v5.84 NDUFB7 Arina Puzriakova Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex I deficiency v3.10 NDUFB7 Arina Puzriakova commented on gene: NDUFB7: PMID: 40025060 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Likely inborn error of metabolism v7.15 NDUFB7 Arina Puzriakova commented on gene: NDUFB7: PMID: 40025060 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Possible mitochondrial disorder - nuclear genes v3.117 NDUFB7 Arina Puzriakova commented on gene: NDUFB7: PMID: 40025060 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Mitochondrial disorder with complex I deficiency v3.10 NDUFB7 Arina Puzriakova commented on gene: NDUFB7
Likely inborn error of metabolism v7.15 NDUFB7 Arina Puzriakova commented on gene: NDUFB7
Possible mitochondrial disorder - nuclear genes v3.117 NDUFB7 Arina Puzriakova commented on gene: NDUFB7
Fetal anomalies v5.83 NDUFB7 Arina Puzriakova commented on gene: NDUFB7
Fetal anomalies v5.83 NDUFB7 Arina Puzriakova Tag Q1_25_ promote_green tag was added to gene: NDUFB7.
Early onset or syndromic epilepsy v7.67 RYR3 Sarah Leigh Publications for gene: RYR3 were set to 25262651; 29667327; 39220738; 39840699
Mitochondrial disorder with complex I deficiency v3.10 NDUFB7 Arina Puzriakova Phenotypes for gene: NDUFB7 were changed from ?Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135 to Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135
Likely inborn error of metabolism v7.15 NDUFB7 Arina Puzriakova Publications for gene: NDUFB7 were set to 33502047; 27626371
Possible mitochondrial disorder - nuclear genes v3.117 NDUFB7 Arina Puzriakova Phenotypes for gene: NDUFB7 were changed from ?Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135 to Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135
Fetal anomalies v5.83 NDUFB7 Arina Puzriakova Phenotypes for gene: NDUFB7 were changed from ?Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135 to Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135
Mitochondrial disorder with complex I deficiency v3.9 NDUFB7 Arina Puzriakova Publications for gene: NDUFB7 were set to 33502047; 27626371
Possible mitochondrial disorder - nuclear genes v3.116 NDUFB7 Arina Puzriakova Publications for gene: NDUFB7 were set to
Fetal anomalies v5.82 NDUFB7 Arina Puzriakova Publications for gene: NDUFB7 were set to 33502047
Mitochondrial disorders v8.14 NDUFB7 Arina Puzriakova Classified gene: NDUFB7 as Amber List (moderate evidence)
Mitochondrial disorders v8.14 NDUFB7 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Although only two unrelated cases have been reported to date (PMID: 33502047, 40025060), there is strong functional data and animal model to support the association. The existence of a therapeutic strategy further supports timely inclusion of this gene on a diagnostic panel.
Mitochondrial disorders v8.14 NDUFB7 Arina Puzriakova Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v8.13 NDUFB7 Arina Puzriakova Phenotypes for gene: NDUFB7 were changed from ?Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135 to Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135
Mitochondrial disorders v8.12 NDUFB7 Arina Puzriakova Publications for gene: NDUFB7 were set to 33502047; 27626371
Mitochondrial disorders v8.11 NDUFB7 Arina Puzriakova Tag watchlist was removed from gene: NDUFB7.
Tag Q1_25_ promote_green tag was added to gene: NDUFB7.
Mitochondrial disorders v8.11 NDUFB7 Arina Puzriakova commented on gene: NDUFB7: PMID: 40025060 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.66 RYR3 Sarah Leigh Publications for gene: RYR3 were set to 25262651; 29667327
Mitochondrial disorders v8.11 NDUFB7 Arina Puzriakova reviewed gene: NDUFB7: Rating: GREEN; Mode of pathogenicity: None; Publications: 40025060; Phenotypes: Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v7.8 AP5B1 Siying Lin gene: AP5B1 was added
gene: AP5B1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: AP5B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP5B1 were set to PMID 40081374
Phenotypes for gene: AP5B1 were set to Macular dystrophy
Mode of pathogenicity for gene: AP5B1 was set to Other
Review for gene: AP5B1 was set to GREEN
Added comment: 2 individuals from 2 families with biallelic loss of function variants and macular dystrophy
Sources: Literature
Retinal disorders v7.8 AP5Z1 Siying Lin gene: AP5Z1 was added
gene: AP5Z1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: AP5Z1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP5Z1 were set to PMID: 40081374
Phenotypes for gene: AP5Z1 were set to Macular dystrophy
Mode of pathogenicity for gene: AP5Z1 was set to Other
Review for gene: AP5Z1 was set to GREEN
Added comment: 14 families affected with macular dystrophy with biallelic AP5Z1 variants (mostly loss of function variants)
Sources: Literature
Intellectual disability v8.155 NAV3 Sarah Leigh Added comment: Comment on publications: PMID: 39708122 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.155 NAV3 Sarah Leigh Publications for gene: NAV3 were set to 38977784; 39038237; 39708122
Intellectual disability v8.154 NAV3 Sarah Leigh Classified gene: NAV3 as Amber List (moderate evidence)
Intellectual disability v8.154 NAV3 Sarah Leigh Gene: nav3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.153 NAV3 Sarah Leigh gene: NAV3 was added
gene: NAV3 was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green, Q1_25_ expert_review tags were added to gene: NAV3.
Mode of inheritance for gene: NAV3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NAV3 were set to 38977784; 39038237; 39708122
Phenotypes for gene: NAV3 were set to recessive neurodevelopmental disorder
Review for gene: NAV3 was set to GREEN
Added comment: At least 11 NAV3 variants have been reported in 11 unrelated families with a neurodevelopmental disorder, with dysmorphism and other features (PMIDs: 38977784;39038237;39708122). The NAV3 variants were homozygous in the affected members of eight of these families, de novo heterozygous NAV3 variants were found in two families (PED4263 & MI01 in PMID: 38977784) and in one case the heterozygous NAV3 variant was inherited from the mother (FM1 in PMID: 38977784). A nav3 knock-zebrafish model resulted in severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, this phenotype was rescued with co-injection of WT NAV3 mRNA, but not pathogenic variant NAV3 mRNA (PMID: 38977784). Varying degrees of intellectual disability was evident in the patients carrying NAV3 variants (severe 2/11, moderate 2/11, mild 7/11)(PMIDs: 38977784;39038237;39708122).
Sources: Literature
Intellectual disability v8.152 TUBGCP2 Arina Puzriakova Tag watchlist was removed from gene: TUBGCP2.
Tag Q1_25_ promote_green tag was added to gene: TUBGCP2.
Intellectual disability v8.152 TUBGCP2 Arina Puzriakova edited their review of gene: TUBGCP2: Added comment: PMID: 40017707 (2025) - reports a 6-year-old girl with lissencephaly caused by compound heterozygous variants in TUBGCP2 (two paternal missense variants: c.178 C>T, c.538T>C and one maternal exon variant: 2–14 deletion). The patient presented with microcephaly, developmental delay, intellectual disability, and seizures. A literature review of 8 patients (including the reported case) with TUBGCP2 variants showed that all exhibited lissencephaly, microcephaly and developmental delay, with most having intellectual disability, seizures, and dysmorphic facial features.

This publication supports inclusion of the TUBGCP2 gene on the intellectual disability panel at the next GMS panel update.; Changed rating: GREEN
Intellectual disability v8.152 TUBGCP2 Arina Puzriakova Added comment: Comment on publications: PMID: 40017707 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.152 TUBGCP2 Arina Puzriakova Publications for gene: TUBGCP2 were set to 31630790
Severe microcephaly v7.19 GTF3C3 Arina Puzriakova Entity copied from Intellectual disability v8.151
Severe microcephaly v7.19 GTF3C3 Arina Puzriakova gene: GTF3C3 was added
gene: GTF3C3 was added to Severe microcephaly. Sources: Expert Review Amber,Victorian Clinical Genetics Services,Literature
Q1_25_ promote_green tags were added to gene: GTF3C3.
Mode of inheritance for gene: GTF3C3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3C3 were set to 28940097; 28097321; 30552426; 40040844
Phenotypes for gene: GTF3C3 were set to Global developmental delay; Intellectual disability; Seizures
Early onset or syndromic epilepsy v7.65 GTF3C3 Arina Puzriakova Entity copied from Intellectual disability v8.151
Early onset or syndromic epilepsy v7.65 GTF3C3 Arina Puzriakova gene: GTF3C3 was added
gene: GTF3C3 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Victorian Clinical Genetics Services,Literature
Q1_25_ promote_green tags were added to gene: GTF3C3.
Mode of inheritance for gene: GTF3C3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3C3 were set to 28940097; 28097321; 30552426; 40040844
Phenotypes for gene: GTF3C3 were set to Global developmental delay; Intellectual disability; Seizures
Intellectual disability v8.151 GTF3C3 Arina Puzriakova Classified gene: GTF3C3 as Amber List (moderate evidence)
Intellectual disability v8.151 GTF3C3 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v8.151 GTF3C3 Arina Puzriakova Gene: gtf3c3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.150 GTF3C3 Arina Puzriakova Tag watchlist was removed from gene: GTF3C3.
Tag Q1_25_ promote_green tag was added to gene: GTF3C3.
Intellectual disability v8.150 GTF3C3 Arina Puzriakova edited their review of gene: GTF3C3: Added comment: - PMID: 39636576 (2025) - 12 individuals from 7 unrelated families were identified with homozygous or compound heterozygous missense variants in GTF3C3 (8 unpublished individuals combined with newly ascertained information from 4 published individuals). The cohort presented with intellectual disability, variable nonfamilial facial features, motor impairments, seizures, and cerebellar/corpus callosum malformations.

- PMID: 40040844 (2025) - 4 patients from 3 unrelated families with biallelic variants in this gene and microcephaly, developmental delay, intellectual disability, seizures and distinctive dysmorphic facies. Knockout zebrafish recapitulated the key clinical symptoms including microcephaly, brain anomalies and seizure susceptibility.; Changed rating: GREEN; Changed publications to: 39636576, 40040844; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.150 GTF3C3 Arina Puzriakova Added comment: Comment on publications: PMID: 40040844 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.150 GTF3C3 Arina Puzriakova Publications for gene: GTF3C3 were set to 28940097, 28097321; 30552426
Intellectual disability v8.149 C12orf66 Arina Puzriakova Classified gene: C12orf66 as Amber List (moderate evidence)
Intellectual disability v8.149 C12orf66 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green the next GMS panel update.
Intellectual disability v8.149 C12orf66 Arina Puzriakova Gene: c12orf66 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.64 C12orf66 Arina Puzriakova Classified gene: C12orf66 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.64 C12orf66 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green the next GMS panel update.
Early onset or syndromic epilepsy v7.64 C12orf66 Arina Puzriakova Gene: c12orf66 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.148 C12orf66 Arina Puzriakova commented on gene: C12orf66: Added new-gene-name tag, new approved HGNC gene symbol for C12orf66 is KICS2
Early onset or syndromic epilepsy v7.63 C12orf66 Arina Puzriakova commented on gene: C12orf66: Added new-gene-name tag, new approved HGNC gene symbol for C12orf66 is KICS2
Intellectual disability v8.148 C12orf66 Arina Puzriakova commented on gene: C12orf66: PMID: 39824192 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.63 C12orf66 Arina Puzriakova commented on gene: C12orf66: PMID: 39824192 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.148 C12orf66 Arina Puzriakova Deleted their comment
Intellectual disability v8.148 C12orf66 Arina Puzriakova Classified gene: C12orf66 as Amber List (moderate evidence)
Intellectual disability v8.148 C12orf66 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v8.148 C12orf66 Arina Puzriakova Gene: c12orf66 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.63 C12orf66 Arina Puzriakova gene: C12orf66 was added
gene: C12orf66 was added to Early onset or syndromic epilepsy. Sources: Literature
new-gene-name, Q1_25_ promote_green tags were added to gene: C12orf66.
Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C12orf66 were set to 39824192
Phenotypes for gene: C12orf66 were set to Intellectual developmental disorder, autosomal recessive 83, OMIM:621100
Review for gene: C12orf66 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM (MIM# 621100)

- PMID: 39824192 (2025) - biallelic variants in KICS2 in 11 individuals from 8 families with intellectual disability. All affected individuals had mild to severe intellectual disability, with 8 individuals also presenting with seizures and 3 (2 families) with hearing impairment. Functional studies in cell culture and zebrafish models provided evidence of pathogenicity, showing impaired mTORC1 regulation and effects on ciliogenesis.
Sources: Literature
Intellectual disability v8.147 C12orf66 Arina Puzriakova gene: C12orf66 was added
gene: C12orf66 was added to Intellectual disability. Sources: Literature
new-gene-name, Q1_25_ promote_green tags were added to gene: C12orf66.
Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C12orf66 were set to 39824192
Phenotypes for gene: C12orf66 were set to Intellectual developmental disorder, autosomal recessive 83, OMIM:621100
Review for gene: C12orf66 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM (MIM# 621100)

- PMID: 39824192 (2025) - biallelic variants in KICS2 in 11 individuals from 8 families with intellectual disability. All affected individuals had mild to severe intellectual disability, with 8 individuals also presenting with seizures and 3 (2 families) with hearing impairment. Functional studies in cell culture and zebrafish models provided evidence of pathogenicity, showing impaired mTORC1 regulation and effects on ciliogenesis.
Sources: Literature
Retinal disorders v7.8 UNC119 Ronnie Wright reviewed gene: UNC119: Rating: AMBER; Mode of pathogenicity: Other; Publications: PMID:30910914; Phenotypes: ; Mode of inheritance: Unknown
Skeletal dysplasia v7.29 SLC13A1 Sarah Leigh Added comment: Comment on publications: PMID: 39925707 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Skeletal dysplasia v7.29 SLC13A1 Sarah Leigh Publications for gene: SLC13A1 were set to 39925707
Skeletal dysplasia v7.29 SLC13A1 Sarah Leigh Classified gene: SLC13A1 as Amber List (moderate evidence)
Skeletal dysplasia v7.29 SLC13A1 Sarah Leigh Gene: slc13a1 has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.8 SLC13A1 Sarah Leigh Added comment: Comment on publications: PMID: 39925707 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Monogenic short stature v1.8 SLC13A1 Sarah Leigh Publications for gene: SLC13A1 were set to 39925707
Monogenic short stature v1.7 SLC13A1 Sarah Leigh Classified gene: SLC13A1 as Amber List (moderate evidence)
Monogenic short stature v1.7 SLC13A1 Sarah Leigh Gene: slc13a1 has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.6 SLC13A1 Sarah Leigh gene: SLC13A1 was added
gene: SLC13A1 was added to Monogenic short stature. Sources: Literature
Q1_25_ promote_green tags were added to gene: SLC13A1.
Mode of inheritance for gene: SLC13A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A1 were set to 39925707
Phenotypes for gene: SLC13A1 were set to impaired sulfate transport and skeletal dysplasia
Review for gene: SLC13A1 was set to GREEN
Added comment: PMID: 39925707 reports five biallelic SLC13A1 variants in five children with skeletal phenotypes from four unrelated families. Inheritance of the variants from the parents has been established in all cases. Functional studies suggested that the SLC13A1 variants resulted in complete loss of sulfate transport activity, evidence of this was seen when two of the probands were tested and found to have reduction in plasma sulfate level and/or increase in urinary sulfate excretion (PMID: 39925707).
Sources: Literature
Skeletal dysplasia v7.28 SLC13A1 Sarah Leigh gene: SLC13A1 was added
gene: SLC13A1 was added to Skeletal dysplasia. Sources: Literature
Q1_25_ promote_green tags were added to gene: SLC13A1.
Mode of inheritance for gene: SLC13A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A1 were set to 39925707
Phenotypes for gene: SLC13A1 were set to impaired sulfate transport and skeletal dysplasia
Review for gene: SLC13A1 was set to GREEN
Added comment: PMID: 39925707 reports five biallelic SLC13A1 variants in five children with skeletal phenotypes from four unrelated families. Inheritance of the variants from the parents has been established in all cases. Functional studies suggested that the SLC13A1 variants resulted in complete loss of sulfate transport activity, evidence of this was seen when two of the probands were tested and found to have reduction in plasma sulfate level and/or increase in urinary sulfate excretion (PMID: 39925707).
Sources: Literature
Hereditary neuropathy or pain disorder v6.164 NOTCH2NL Arina Puzriakova commented on gene: NOTCH2NL
Hereditary neuropathy or pain disorder v6.164 NOTCH2NL Arina Puzriakova Tag new-gene-name tag was added to gene: NOTCH2NL.
Early onset or syndromic epilepsy v7.62 SPOUT1 Sarah Leigh Classified gene: SPOUT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.62 SPOUT1 Sarah Leigh Gene: spout1 has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.5 SPOUT1 Sarah Leigh Classified gene: SPOUT1 as Amber List (moderate evidence)
Monogenic short stature v1.5 SPOUT1 Sarah Leigh Gene: spout1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.62 SPOUT1 Sarah Leigh Added comment: Comment on publications: PMID: 39962046 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.62 SPOUT1 Sarah Leigh Publications for gene: SPOUT1 were set to 39962046
Intellectual disability v8.146 SPOUT1 Sarah Leigh Added comment: Comment on publications: PMID: 39962046 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.146 SPOUT1 Sarah Leigh Publications for gene: SPOUT1 were set to 39962046
Monogenic short stature v1.4 SPOUT1 Sarah Leigh Added comment: Comment on publications: PMID: 39962046 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Monogenic short stature v1.4 SPOUT1 Sarah Leigh Publications for gene: SPOUT1 were set to 39962046
Intellectual disability v8.145 SPOUT1 Sarah Leigh Classified gene: SPOUT1 as Amber List (moderate evidence)
Intellectual disability v8.145 SPOUT1 Sarah Leigh Gene: spout1 has been classified as Amber List (Moderate Evidence).
Monogenic short stature v1.3 SPOUT1 Sarah Leigh gene: SPOUT1 was added
gene: SPOUT1 was added to Monogenic short stature. Sources: Literature
Q1_25_ promote_green tags were added to gene: SPOUT1.
Mode of inheritance for gene: SPOUT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPOUT1 were set to 39962046
Phenotypes for gene: SPOUT1 were set to SPOUT1 Associated Development delay Microcephaly Seizures Short stature
Review for gene: SPOUT1 was set to GREEN
Added comment: PMID: 39962046 reports the association of biallelic SPOUT1 variants with SPOUT1 Associated Development delay Microcephaly Seizures Short stature. In this study, a total of 18 SPOUT1 variants were found in 28 individuals from 21 unrelated families. Intellectual disability was evident in 10/10 families where it could be ascertained, seizures were reported in 16/21 of the families and short stature was seen in 13/15 families where it could be measured.
SPOUT1 variant zebra fish models showed reduction in larval head size with concomitant apoptosis and the human SPOUT1 missense variants were pathogenic in complementation assays in zebrafish (PMID: 39962046).
Sources: Literature
Early onset or syndromic epilepsy v7.61 SPOUT1 Sarah Leigh gene: SPOUT1 was added
gene: SPOUT1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_25_ promote_green tags were added to gene: SPOUT1.
Mode of inheritance for gene: SPOUT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPOUT1 were set to 39962046
Phenotypes for gene: SPOUT1 were set to SPOUT1 Associated Development delay Microcephaly Seizures Short stature
Review for gene: SPOUT1 was set to GREEN
Added comment: PMID: 39962046 reports the association of biallelic SPOUT1 variants with SPOUT1 Associated Development delay Microcephaly Seizures Short stature. In this study, a total of 18 SPOUT1 variants were found in 28 individuals from 21 unrelated families. Intellectual disability was evident in 10/10 families where it could be ascertained, seizures were reported in 16/21 of the families and short stature was seen in 13/15 families where it could be measured.
SPOUT1 variant zebra fish models showed reduction in larval head size with concomitant apoptosis and the human SPOUT1 missense variants were pathogenic in complementation assays in zebrafish (PMID: 39962046).
Sources: Literature
Intellectual disability v8.144 SPOUT1 Sarah Leigh gene: SPOUT1 was added
gene: SPOUT1 was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: SPOUT1.
Mode of inheritance for gene: SPOUT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPOUT1 were set to 39962046
Phenotypes for gene: SPOUT1 were set to SPOUT1 Associated Development delay Microcephaly Seizures Short stature
Review for gene: SPOUT1 was set to GREEN
Added comment: PMID: 39962046 reports the association of biallelic SPOUT1 variants with SPOUT1 Associated Development delay Microcephaly Seizures Short stature. In this study, a total of 18 SPOUT1 variants were found in 28 individuals from 21 unrelated families. Intellectual disability was evident in 10/10 families where it could be ascertained, seizures were reported in 16/21 of the families and short stature was seen in 13/15 families where it could be measured.
SPOUT1 variant zebra fish models showed reduction in larval head size with concomitant apoptosis and the human SPOUT1 missense variants were pathogenic in complementation assays in zebrafish (PMID: 39962046).
Sources: Literature
Differences in sex development v4.12 DMRT1 Sarah Leigh Publications for gene: DMRT1 were set to 11870074; 26139570; 24934491; 39936125
Differences in sex development v4.11 DMRT1 Sarah Leigh edited their review of gene: DMRT1: Added comment: Variants affecting DMRT1 have been reported in cases with 46,XY disorders/differences of sex development. PMID: 24934491 reports NM_021951.3(DMRT1):c.671A>G (p.Asn224Ser) in 2 unrelated azoospermic men with complete bilateral Sertoli cell-only syndrome and decreased testicular volume by ultrasound. PMID: 26139570 reports NM_021951.2 c.-223_-219CGAAA>T in the promoter of DMRT1, which is a region shown to be involved in the repression of Dmrt1 expression in rat and mouse Sertoli cells (PMID:11870074). Therefore this promoter variants could result in disruption of DMRT1 regulation. PMID: 39936125 reports four different deletions, which all encompass the DMRT1 region (9p24.3p23 - 9p24) in four unrelated cases with gonadal dysgenesis and .; Changed rating: AMBER
Differences in sex development v4.11 DMRT1 Sarah Leigh Added comment: Comment on publications: PMID: 39936125 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Differences in sex development v4.11 DMRT1 Sarah Leigh Publications for gene: DMRT1 were set to 26139570; 24934491; 39936125
Differences in sex development v4.10 DMRT1 Sarah Leigh Classified gene: DMRT1 as Amber List (moderate evidence)
Differences in sex development v4.10 DMRT1 Sarah Leigh Gene: dmrt1 has been classified as Amber List (Moderate Evidence).
Differences in sex development v4.9 DMRT1 Sarah Leigh Phenotypes for gene: DMRT1 were changed from Gender Assignment Gene Panel (UKGTN) to 46,XY disorders/differences of sex development
Differences in sex development v4.8 DMRT1 Sarah Leigh Publications for gene: DMRT1 were set to 26139570
Differences in sex development v4.7 DMRT1 Sarah Leigh Mode of inheritance for gene: DMRT1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic short stature v1.2 RSPRY1 Arina Puzriakova Entity copied from Intellectual disability v8.143
Monogenic short stature v1.2 RSPRY1 Arina Puzriakova gene: RSPRY1 was added
gene: RSPRY1 was added to Monogenic short stature. Sources: Expert Review Amber,Literature
Q1_25_ promote_green tags were added to gene: RSPRY1.
Mode of inheritance for gene: RSPRY1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSPRY1 were set to 26365341; 30063090; 38562122; 39940902
Phenotypes for gene: RSPRY1 were set to Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, OMIM:616723
Skeletal dysplasia v7.27 RSPRY1 Arina Puzriakova Entity copied from Intellectual disability v8.143
Skeletal dysplasia v7.27 RSPRY1 Arina Puzriakova gene: RSPRY1 was added
gene: RSPRY1 was added to Skeletal dysplasia. Sources: Expert Review Amber,Literature
Q1_25_ promote_green tags were added to gene: RSPRY1.
Mode of inheritance for gene: RSPRY1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSPRY1 were set to 26365341; 30063090; 38562122; 39940902
Phenotypes for gene: RSPRY1 were set to Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, OMIM:616723
Intellectual disability v8.142 RSPRY1 Arina Puzriakova Tag watchlist was removed from gene: RSPRY1.
Tag Q1_25_ promote_green tag was added to gene: RSPRY1.
Intellectual disability v8.142 RSPRY1 Arina Puzriakova Classified gene: RSPRY1 as Amber List (moderate evidence)
Intellectual disability v8.142 RSPRY1 Arina Puzriakova Added comment: Comment on list classification: At least 5 unrelated families have been reported in the literature with biallelic variants in this gene, presenting with spondyloepimetaphyseal dysplasia. Sufficient to rate Green at the next GMS panel update.
Intellectual disability v8.142 RSPRY1 Arina Puzriakova Gene: rspry1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.141 RSPRY1 Arina Puzriakova Added comment: Comment on publications: PMID: 39940902 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.141 RSPRY1 Arina Puzriakova Publications for gene: RSPRY1 were set to 26365341; 30063090; 38562122; 39940902
Intellectual disability v8.140 RSPRY1 Arina Puzriakova Phenotypes for gene: RSPRY1 were changed from Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, 616585 to Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, OMIM:616723
Intellectual disability v8.139 RSPRY1 Arina Puzriakova Publications for gene: RSPRY1 were set to 26365341; 30914295
Intellectual disability v8.138 RSPRY1 Arina Puzriakova reviewed gene: RSPRY1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26365341, 30063090, 38562122, 39940902; Phenotypes: Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, OMIM:616723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.60 DALRD3 Arina Puzriakova Tag watchlist tag was added to gene: DALRD3.
Intellectual disability v8.138 DALRD3 Arina Puzriakova Classified gene: DALRD3 as Amber List (moderate evidence)
Intellectual disability v8.138 DALRD3 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as only 2 families have been reported to date.
Intellectual disability v8.138 DALRD3 Arina Puzriakova Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.60 DALRD3 Arina Puzriakova Classified gene: DALRD3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.60 DALRD3 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as only 2 families have been reported to date.
Early onset or syndromic epilepsy v7.60 DALRD3 Arina Puzriakova Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.59 DALRD3 Arina Puzriakova Added comment: Comment on publications: PMID: 39482881 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.59 DALRD3 Arina Puzriakova Publications for gene: DALRD3 were set to 32427860
Early onset or syndromic epilepsy v7.58 DALRD3 Arina Puzriakova commented on gene: DALRD3: PMID: 39482881 - second family identified with an individual with a homozygous missense variant in DALRD3 (c.1549C>T, p.(Arg517Cys)) who displayed severe developmental delay, cognitive deficiencies, and multifocal epilepsy. Phenotype was consistent with previously reported cases but less severe which is consistent with the variant types identified. Patient fibroblasts showed reduced levels of DALRD3 protein compared to WT indicating the variant alters the structure of DALRD3.
Intellectual disability v8.137 DALRD3 Arina Puzriakova Added comment: Comment on publications: PMID: 39482881 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.137 DALRD3 Arina Puzriakova Publications for gene: DALRD3 were set to 32427860
Intellectual disability v8.136 DALRD3 Arina Puzriakova changed review comment from: Second family identified with an individual with a homozygous missense variant in DALRD3 (c.1549C>T, p.(Arg517Cys)) who displayed severe developmental delay, cognitive deficiencies, and multifocal epilepsy. Phenotype was consistent with previously reported cases but less severe which is consistent with the variant types identified. Patient fibroblasts showed reduced levels of DALRD3 protein compared to WT indicating the variant alters the structure of DALRD3.; to: PMID: 39482881 - second family identified with an individual with a homozygous missense variant in DALRD3 (c.1549C>T, p.(Arg517Cys)) who displayed severe developmental delay, cognitive deficiencies, and multifocal epilepsy. Phenotype was consistent with previously reported cases but less severe which is consistent with the variant types identified. Patient fibroblasts showed reduced levels of DALRD3 protein compared to WT indicating the variant alters the structure of DALRD3.
Intellectual disability v8.136 DALRD3 Arina Puzriakova commented on gene: DALRD3: Second family identified with an individual with a homozygous missense variant in DALRD3 (c.1549C>T, p.(Arg517Cys)) who displayed severe developmental delay, cognitive deficiencies, and multifocal epilepsy. Phenotype was consistent with previously reported cases but less severe which is consistent with the variant types identified. Patient fibroblasts showed reduced levels of DALRD3 protein compared to WT indicating the variant alters the structure of DALRD3.
Early onset or syndromic epilepsy v7.58 DALRD3 Arina Puzriakova Deleted their comment
Hereditary ataxia with onset in adulthood v7.13 SPR Arina Puzriakova Tag Q1_25_ MOI tag was added to gene: SPR.
Tag watchlist_moi tag was added to gene: SPR.
Adult onset dystonia, chorea or related movement disorder v4.6 SPR Arina Puzriakova Tag Q1_25_ MOI tag was added to gene: SPR.
Tag watchlist_moi tag was added to gene: SPR.
Adult onset dystonia, chorea or related movement disorder v4.6 SPR Arina Puzriakova Added comment: Comment on mode of inheritance: Sepiapterin reductase deficiency typically follows an autosomal recessive pattern of inheritance. Two cases with different heterozygous variants have been reported (PMID: 29147684, 15241655) although with reduced penetrance in the familial cases and mild form of the disorder in the singleton.

Overall additional evidence is required to conclusively make an association with monoallelic variants and therefore suggesting the MOI is also changed from 'Both mono- and biallelic' to 'Biallelic', with a watchlist_moi tag to monitor for more dominant cases.
Adult onset dystonia, chorea or related movement disorder v4.6 SPR Arina Puzriakova Mode of inheritance for gene: SPR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v7.13 SPR Arina Puzriakova Added comment: Comment on mode of inheritance: Sepiapterin reductase deficiency typically follows an autosomal recessive pattern of inheritance. Two cases with different heterozygous variants have been reported (PMID: 29147684, 15241655) although with reduced penetrance in the familial cases and mild form of the disorder in the singleton.

Overall additional evidence is required to conclusively make an association with monoallelic variants and therefore suggesting the MOI is also changed from 'Both mono- and biallelic' to 'Biallelic', with a watchlist_moi tag to monitor for more dominant cases.
Hereditary ataxia with onset in adulthood v7.13 SPR Arina Puzriakova Mode of inheritance for gene: SPR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.58 SPR Arina Puzriakova Added comment: Comment on mode of inheritance: Sepiapterin reductase deficiency typically follows an autosomal recessive pattern of inheritance. Two cases with different heterozygous variants have been reported (PMID: 29147684, 15241655) although with reduced penetrance in the familial cases and mild form of the disorder in the singleton.

Overall additional evidence is required to conclusively make an association with monoallelic variants and therefore updating the MOI from 'Both mono- and biallelic' to 'Biallelic'
Early onset or syndromic epilepsy v7.58 SPR Arina Puzriakova Mode of inheritance for gene: SPR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v7.12 SPR Arina Puzriakova Added comment: Comment on mode of inheritance: Sepiapterin reductase deficiency typically follows an autosomal recessive pattern of inheritance. Two cases with different heterozygous variants have been reported (PMID: 29147684, 15241655) although with reduced penetrance in the familial cases and mild form of the disorder in the singleton.

Overall additional evidence is required to conclusively make an association with monoallelic variants and therefore updating the MOI from 'Both mono- and biallelic' to 'Biallelic'
Adult onset neurodegenerative disorder v7.12 SPR Arina Puzriakova Mode of inheritance for gene: SPR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v3.15 SPR Arina Puzriakova Added comment: Comment on mode of inheritance: Sepiapterin reductase deficiency typically follows an autosomal recessive pattern of inheritance. Two cases with different heterozygous variants have been reported (PMID: 29147684, 15241655) although with reduced penetrance in the familial cases and mild form of the disorder in the singleton.

Overall additional evidence is required to conclusively make an association with monoallelic variants and therefore updating the MOI from 'Both mono- and biallelic' to 'Biallelic'
Paroxysmal central nervous system disorders v3.15 SPR Arina Puzriakova Mode of inheritance for gene: SPR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Brain channelopathy v1.82 SPR Arina Puzriakova Added comment: Comment on mode of inheritance: Sepiapterin reductase deficiency typically follows an autosomal recessive pattern of inheritance. Two cases with different heterozygous variants have been reported (PMID: 29147684, 15241655) although with reduced penetrance in the familial cases and mild form of the disorder in the singleton.

Overall additional evidence is required to conclusively make an association with monoallelic variants and therefore updating the MOI from 'Both mono- and biallelic' to 'Biallelic'
Brain channelopathy v1.82 SPR Arina Puzriakova Mode of inheritance for gene: SPR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v6.7 SPR Arina Puzriakova Tag Q1_25_ MOI tag was added to gene: SPR.
Tag watchlist_moi tag was added to gene: SPR.
Childhood onset dystonia, chorea or related movement disorder v6.7 SPR Arina Puzriakova Added comment: Comment on mode of inheritance: Sepiapterin reductase deficiency typically follows an autosomal recessive pattern of inheritance. Two cases with different heterozygous variants have been reported (PMID: 29147684, 15241655) although with reduced penetrance in the familial cases and mild form of the disorder in the singleton.

Overall additional evidence is required to conclusively make an association with monoallelic variants and therefore suggesting the MOI is changed from 'Both mono- and biallelic' to 'Biallelic' at the next GMS panel update, with a watchlist_moi tag to monitor for more dominant cases.
Childhood onset dystonia, chorea or related movement disorder v6.7 SPR Arina Puzriakova Mode of inheritance for gene: SPR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset dystonia, chorea or related movement disorder v4.5 SPR Arina Puzriakova Tag Q1_25_ demote_red tag was added to gene: SPR.
Tag Q1_25_ expert_review tag was added to gene: SPR.
Hereditary ataxia with onset in adulthood v7.12 SPR Arina Puzriakova Tag Q1_25_ demote_red tag was added to gene: SPR.
Tag Q1_25_ expert_review tag was added to gene: SPR.
Hereditary ataxia with onset in adulthood v7.12 SPR Arina Puzriakova reviewed gene: SPR: Rating: ; Mode of pathogenicity: None; Publications: 26131547; Phenotypes: Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716; Mode of inheritance: None
Adult onset dystonia, chorea or related movement disorder v4.5 SPR Arina Puzriakova reviewed gene: SPR: Rating: ; Mode of pathogenicity: None; Publications: 26131547; Phenotypes: Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716; Mode of inheritance: None
Childhood onset dystonia, chorea or related movement disorder v6.6 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Dopa-Responsive Dystonia; Movement disorder, autonomic dysfunction, developmental delay, behavioural difficulties; Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, 612716; Sepiapterin reductase deficiency; paediatric form of dopa responsive dystonia to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Intellectual disability v8.136 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from DOPA-RESPONSIVE DYSTONIA DUE TO SEPIAPTERIN REDUCTASE DEFICIENCY to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Hereditary ataxia with onset in adulthood v7.12 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Dystonia, dopa-responsive, due to sepiapterin reductase deficiency 612716; Dopa-responsive dystonia due to sepiaterin reductase deficiency, 612716 to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Early onset or syndromic epilepsy v7.57 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Dystonia, dopa-responsive, due to sepiapterin reductase deficiency 612716 to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Fetal anomalies v5.81 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from DOPA-RESPONSIVE DYSTONIA DUE TO SEPIAPTERIN REDUCTASE DEFICIENCY to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Likely inborn error of metabolism v7.14 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Intellectual disability; Early onset dystonia; Sepiapterin reductase deficiency (Disorders of pterin metabolism); Parkinson Disease and Complex Parkinsonism to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716; Sepiapterin reductase deficiency (Disorders of pterin metabolism)
Undiagnosed metabolic disorders v1.625 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Sepiapterin reductase deficiency (Disorders of pterin metabolism); Early onset dystonia; Intellectual disability; Parkinson Disease and Complex Parkinsonism to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716; Sepiapterin reductase deficiency (Disorders of pterin metabolism)
Adult onset neurodegenerative disorder v7.11 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from paediatric form of dopa responsive dystonia; Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, 612716; Dystonia, dopa-responsive, due to sepiapterin reductase deficiency 612716; Dopa-Responsive Dystonia to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Paroxysmal central nervous system disorders v3.14 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, 612716 to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Early onset dystonia v1.148 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Dopa-Responsive Dystonia; Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, 612716; paediatric form of dopa responsive dystonia to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716; paediatric form of dopa responsive dystonia
Brain channelopathy v1.81 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Dystonia, dopa-responsive, due to sepiapterin reductase deficiency 612716 to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Parkinson Disease and Complex Parkinsonism v1.127 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Dopa-Responsive Dystonia; Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, 612716; paediatric form of dopa responsive dystonia to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716; paediatric form of dopa responsive dystonia
Neurotransmitter disorders v1.10 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, 612716; Movement disorder, autonomic dysfunction, developmental delay, behavioural difficulties; Dopa-Responsive Dystonia; Sepiapterin reductase deficiency to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716; Movement disorder, autonomic dysfunction, developmental delay, behavioural difficulties; Sepiapterin reductase deficiency
Retinal disorders v7.8 AP5M1 Cassandra Smith gene: AP5M1 was added
gene: AP5M1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: AP5M1 was set to BIALLELIC, autosomal or pseudoautosomal
Review for gene: AP5M1 was set to GREEN
Added comment: Not yet findable in PubMed

Paper: https://www.cell.com/ajhg/fulltext/S0002-9297(25)00062-X

Identified three patients from three different families with biallelic LOF variants and macular dystrophy
Sources: Literature
Congenital hypothyroidism v2.23 STRTS Sarah Leigh commented on Region: STRTS: The curator_removed tag has been added to this entry on PanelApp, because this entity is a short tandem repeat (STR) and not a region. This STR will be added to PanelApp in the future.
Congenital hypothyroidism v2.23 STRTS Sarah Leigh Tag curated_removed tag was added to Region: STRTS.
Hereditary spastic paraplegia v1.314 SPAST Sarah Leigh Added comment: Comment on publications: PMID: 39731306 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Hereditary spastic paraplegia v1.314 SPAST Sarah Leigh Publications for gene: SPAST were set to 26094131; 23897027; 10610178; 10891911; 11039577; 34935948
Hereditary neuropathy v1.497 SPAST Sarah Leigh Added comment: Comment on publications: PMID: 39731306 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Hereditary neuropathy v1.497 SPAST Sarah Leigh Publications for gene: SPAST were set to 28572275
Hereditary neuropathy v1.496 SPAST Sarah Leigh Mode of inheritance for gene: SPAST was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v7.8 SPAST Sarah Leigh Added comment: Comment on publications: PMID: 39731306 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Childhood onset hereditary spastic paraplegia v7.8 SPAST Sarah Leigh Publications for gene: SPAST were set to Hazan et al (1999); 10610178; 10699187; 11039577; 10980739; 15210521; 16832076
Childhood onset hereditary spastic paraplegia v7.7 SPAST Sarah Leigh Tag Q1_25_ MOI tag was added to gene: SPAST.
Hereditary neuropathy or pain disorder v6.164 SPAST Sarah Leigh Added comment: Comment on publications: PMID: 39731306 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Hereditary neuropathy or pain disorder v6.164 SPAST Sarah Leigh Publications for gene: SPAST were set to 28572275
Hereditary neuropathy or pain disorder v6.163 SPAST Sarah Leigh Tag Q1_25_ MOI tag was added to gene: SPAST.
Hereditary neuropathy or pain disorder v6.163 SPAST Sarah Leigh edited their review of gene: SPAST: Added comment: Numerous heterozygous SPAST variants have been associated with Spastic paraplegia 4, autosomal dominant (OMIM:182601). PMID: 39731306 reports five homozygous SPAST variants in nine individuals from six families with spastic paraplegia and neurodegeneration. Amongst the homozygous children, all had lower limb spasticity, 5/6 had upper limb spasticity and 3/6 had severe intellectual disability. Evidence of consanguinity was evident in five of the families and the parents of the homozygous children were heterozygous for the SPAST variant found in the child, these carrier parents were asymptomatic in all but one the families studied.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia v1.313 SPAST Sarah Leigh Mode of inheritance for gene: SPAST was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia v1.312 SPAST Sarah Leigh reviewed gene: SPAST: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.495 SPAST Sarah Leigh reviewed gene: SPAST: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v7.7 SPAST Sarah Leigh reviewed gene: SPAST: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v8.135 SPAST Sarah Leigh Tag Q1_25_ MOI tag was added to gene: SPAST.
Tag Q1_25_ promote_green tag was added to gene: SPAST.
Intellectual disability v8.135 SPAST Sarah Leigh edited their review of gene: SPAST: Added comment: Numerous heterozygous SPAST variants have been associated with Spastic paraplegia 4, autosomal dominant (OMIM:182601). PMID: 39731306 reports five homozygous SPAST variants in nine individuals from six families with spastic paraplegia and neurodegeneration. Amongst the homozygous children, all had lower limb spasticity, 5/6 had upper limb spasticity and 3/6 had severe intellectual disability. Evidence of consanguinity was evident in five of the families and the parents of the homozygous children were heterozygous for the SPAST variant found in the child, these carrier parents were asymptomatic in all but one the families studied.; Changed rating: GREEN; Changed publications to: 39731306; Changed phenotypes to: Spastic paraplegia 4, autosomal dominant, OMIM:182601; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.56 PTPMT1 Arina Puzriakova Classified gene: PTPMT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.56 PTPMT1 Arina Puzriakova Gene: ptpmt1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v8.11 PTPMT1 Arina Puzriakova Classified gene: PTPMT1 as Amber List (moderate evidence)
Mitochondrial disorders v8.11 PTPMT1 Arina Puzriakova Gene: ptpmt1 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.115 PTPMT1 Arina Puzriakova Classified gene: PTPMT1 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.115 PTPMT1 Arina Puzriakova Gene: ptpmt1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v7.18 PTPMT1 Arina Puzriakova Classified gene: PTPMT1 as Amber List (moderate evidence)
Severe microcephaly v7.18 PTPMT1 Arina Puzriakova Gene: ptpmt1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v7.21 PTPMT1 Arina Puzriakova Classified gene: PTPMT1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v7.21 PTPMT1 Arina Puzriakova Gene: ptpmt1 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.114 PTPMT1 Arina Puzriakova gene: PTPMT1 was added
gene: PTPMT1 was added to Possible mitochondrial disorder - nuclear genes. Sources: Literature
watchlist tags were added to gene: PTPMT1.
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645
Phenotypes for gene: PTPMT1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: PTPMT1 was set to AMBER
Added comment: New gene-disease association. Currently not associated with any phenotype in OMIM or G2P.

PMID:39279645 (2025) - 6 individuals from 3 unrelated families identified with biallelic variants in this gene. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome, however there was variability in the overall clinical presentation between families. Features include developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes.

Patient from Family 1 harboured a homozygous missense variant (c.65A>C) while Family 2 and 3 carried the same homozygous variant (c.255G>C) and were shown to share some common ancestry using DNA microarray analysis.

Knockout zebrafish model displayed abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.

Overall can be classified as Amber on the basis that two families were shown to be distantly related and no specific features were observed universally across all cases (GDD was mild in 5/6 individuals so outside the scope of the ID panel).
Sources: Literature
Severe microcephaly v7.17 PTPMT1 Arina Puzriakova gene: PTPMT1 was added
gene: PTPMT1 was added to Severe microcephaly. Sources: Literature
watchlist tags were added to gene: PTPMT1.
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645
Phenotypes for gene: PTPMT1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: PTPMT1 was set to AMBER
Added comment: New gene-disease association. Currently not associated with any phenotype in OMIM or G2P.

PMID:39279645 (2025) - 6 individuals from 3 unrelated families identified with biallelic variants in this gene. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome, however there was variability in the overall clinical presentation between families. Features include developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes.

Patient from Family 1 harboured a homozygous missense variant (c.65A>C) while Family 2 and 3 carried the same homozygous variant (c.255G>C) and were shown to share some common ancestry using DNA microarray analysis.

Knockout zebrafish model displayed abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.

Overall can be classified as Amber on the basis that two families were shown to be distantly related and no specific features were observed universally across all cases (GDD was mild in 5/6 individuals so outside the scope of the ID panel).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v7.20 PTPMT1 Arina Puzriakova gene: PTPMT1 was added
gene: PTPMT1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
watchlist tags were added to gene: PTPMT1.
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645
Phenotypes for gene: PTPMT1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: PTPMT1 was set to AMBER
Added comment: New gene-disease association. Currently not associated with any phenotype in OMIM or G2P.

PMID:39279645 (2025) - 6 individuals from 3 unrelated families identified with biallelic variants in this gene. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome, however there was variability in the overall clinical presentation between families. Features include developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes.

Patient from Family 1 harboured a homozygous missense variant (c.65A>C) while Family 2 and 3 carried the same homozygous variant (c.255G>C) and were shown to share some common ancestry using DNA microarray analysis.

Knockout zebrafish model displayed abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.

Overall can be classified as Amber on the basis that two families were shown to be distantly related and no specific features were observed universally across all cases (GDD was mild in 5/6 individuals so outside the scope of the ID panel).
Sources: Literature
Early onset or syndromic epilepsy v7.55 PTPMT1 Arina Puzriakova gene: PTPMT1 was added
gene: PTPMT1 was added to Early onset or syndromic epilepsy. Sources: Literature
watchlist tags were added to gene: PTPMT1.
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645
Phenotypes for gene: PTPMT1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: PTPMT1 was set to AMBER
Added comment: New gene-disease association. Currently not associated with any phenotype in OMIM or G2P.

PMID:39279645 (2025) - 6 individuals from 3 unrelated families identified with biallelic variants in this gene. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome, however there was variability in the overall clinical presentation between families. Features include developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes.

Patient from Family 1 harboured a homozygous missense variant (c.65A>C) while Family 2 and 3 carried the same homozygous variant (c.255G>C) and were shown to share some common ancestry using DNA microarray analysis.

Knockout zebrafish model displayed abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.

Overall can be classified as Amber on the basis that two families were shown to be distantly related and no specific features were observed universally across all cases (GDD was mild in 5/6 individuals so outside the scope of the ID panel).
Sources: Literature
Mitochondrial disorders v8.10 PTPMT1 Arina Puzriakova gene: PTPMT1 was added
gene: PTPMT1 was added to Mitochondrial disorders. Sources: Literature
watchlist tags were added to gene: PTPMT1.
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645
Phenotypes for gene: PTPMT1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: PTPMT1 was set to AMBER
Added comment: New gene-disease association. Currently not associated with any phenotype in OMIM or G2P.

PMID:39279645 (2025) - 6 individuals from 3 unrelated families identified with biallelic variants in this gene. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome, however there was variability in the overall clinical presentation between families. Features include developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes.

Patient from Family 1 harboured a homozygous missense variant (c.65A>C) while Family 2 and 3 carried the same homozygous variant (c.255G>C) and were shown to share some common ancestry using DNA microarray analysis.

Knockout zebrafish model displayed abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.

Overall can be classified as Amber on the basis that two families were shown to be distantly related and no specific features were observed universally across all cases (GDD was mild in 5/6 individuals so outside the scope of the ID panel).
Sources: Literature
Intellectual disability v8.135 PTPMT1 Arina Puzriakova gene: PTPMT1 was added
gene: PTPMT1 was added to Intellectual disability. Sources: Literature
watchlist tags were added to gene: PTPMT1.
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645
Phenotypes for gene: PTPMT1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: PTPMT1 was set to AMBER
Added comment: New gene-disease association. Currently not associated with any phenotype in OMIM or G2P.

PMID:39279645 (2025) - 6 individuals from 3 unrelated families identified with biallelic variants in this gene. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome, however there was variability in the overall clinical presentation between families. Features include developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes.

Patient from Family 1 harboured a homozygous missense variant (c.65A>C) while Family 2 and 3 carried the same homozygous variant (c.255G>C) and were shown to share some common ancestry using DNA microarray analysis.

Knockout zebrafish model displayed abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.

Overall can be classified as Amber on the basis that two families were shown to be distantly related and no specific features were observed universally across all cases (GDD was mild in 5/6 individuals so outside the scope of the ID panel).
Sources: Literature
Intellectual disability v8.134 SPAST Sarah Leigh Phenotypes for gene: SPAST were changed from Spastic paraplegia 4, autosomal dominant, 182601 to Spastic paraplegia 4, autosomal dominant, OMIM:182601; hereditary spastic paraplegia 4, MONDO:0008438
Intellectual disability v8.133 SPAST Sarah Leigh Added comment: Comment on publications: PMID: 39731306 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.133 SPAST Sarah Leigh Publications for gene: SPAST were set to
Intellectual disability v8.132 SPAST Sarah Leigh Classified gene: SPAST as Amber List (moderate evidence)
Intellectual disability v8.132 SPAST Sarah Leigh Gene: spast has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v7.7 LSM7 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v6.9
Childhood onset hereditary spastic paraplegia v7.7 LSM7 Arina Puzriakova gene: LSM7 was added
gene: LSM7 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: LSM7.
Mode of inheritance for gene: LSM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM7 were set to 35047835; 39420558
Phenotypes for gene: LSM7 were set to Leukodystrophy, MONDO:0019046
Ataxia and cerebellar anomalies - narrow panel v7.19 LSM7 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v6.9
Ataxia and cerebellar anomalies - narrow panel v7.19 LSM7 Arina Puzriakova gene: LSM7 was added
gene: LSM7 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: LSM7.
Mode of inheritance for gene: LSM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM7 were set to 35047835; 39420558
Phenotypes for gene: LSM7 were set to Leukodystrophy, MONDO:0019046
Intellectual disability v8.131 LSM7 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v6.9
Intellectual disability v8.131 LSM7 Arina Puzriakova gene: LSM7 was added
gene: LSM7 was added to Intellectual disability. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: LSM7.
Mode of inheritance for gene: LSM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM7 were set to 35047835; 39420558
Phenotypes for gene: LSM7 were set to Leukodystrophy, MONDO:0019046
White matter disorders and cerebral calcification - narrow panel v6.9 LSM7 Arina Puzriakova Tag watchlist tag was added to gene: LSM7.
White matter disorders and cerebral calcification - narrow panel v6.9 LSM7 Arina Puzriakova Classified gene: LSM7 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v6.9 LSM7 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as one individual died in utero and their phenotype could not be compared to the other two cases. Additionally, although likely homozygous based on the carrier status of the parents, the genotype of this individual is presumed and not confirmed. Overall the evidence is borderline Amber/Green so adding a watchlist tag to monitor for additional studies.
White matter disorders and cerebral calcification - narrow panel v6.9 LSM7 Arina Puzriakova Gene: lsm7 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v6.8 LSM7 Arina Puzriakova edited their review of gene: LSM7: Added comment: Additional family identified with compound heterozygous missense variants in this gene (PMID:39420558). The proband presented with neurodevelopmental defects, leukodystrophy, spastic quadriparesis, and cerebellar atrophy. Authors state that this individual harboured heterozygous variants of each of the previously reported homozygous variants identified in patients from PMID:35047835.; Changed publications to: 35047835, 39420558; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v7.10 POLG Sarah Leigh Added comment: Comment on publications: PMID: 39498811 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Adult onset neurodegenerative disorder v7.10 POLG Sarah Leigh Publications for gene: POLG were set to
Adult onset neurodegenerative disorder v7.9 POLG Sarah Leigh Classified gene: POLG as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v7.9 POLG Sarah Leigh Gene: polg has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v7.8 POLG Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: POLG.
Adult onset neurodegenerative disorder v7.8 POLG Sarah Leigh edited their review of gene: POLG: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v7.8 POLG Sarah Leigh changed review comment from: In their study of a 1185 Spanish Parkinson disease patients, PMID: 39498811 report eleven individuals carrying heterozygous POLG variants. Seven POLG variants were identified in the patients, including the co-occurrence of c.752C>T, p.Thr251Ile and c.1760C>Tp.Pro587Leu (NM_002693.3), which are in cis. The phenotypic features of these patients included motor fluctuations (81.8%), dyskinesias (70%), cognitive impairment (80%), rapid eye movement sleep behavior disorder (70%) and olfactory dysfunction (71.4%). Ataxia or peripheral neuropathy were not reported for these patients (PMID: 39498811).; to: In their study of a 1185 Spanish Parkinson disease patients, PMID: 39498811 report eleven individuals carrying heterozygous POLG variants. Seven POLG variants were identified in the patients, including the co-occurrence of c.752C>T, p.Thr251Ile and c.1760C>Tp.Pro587Leu (NM_002693.3), which are in cis. The phenotypic features of these patients included motor fluctuations (81.8%), dyskinesias (70%), cognitive impairment (80%), rapid eye movement sleep behavior disorder (70%) and olfactory dysfunction (71.4%). Ataxia or peripheral neuropathy were not reported for these patients (PMID: 39498811).
Adult onset neurodegenerative disorder v7.8 POLG Sarah Leigh reviewed gene: POLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 39498811; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v5.48 TMEM199 Eleanor Williams commented on gene: TMEM199
DDG2P v5.48 TMEM199 Eleanor Williams Tag new-gene-name tag was added to gene: TMEM199.
Likely inborn error of metabolism v7.13 TMEM199 Eleanor Williams commented on gene: TMEM199
Likely inborn error of metabolism v7.13 TMEM199 Eleanor Williams Tag new-gene-name tag was added to gene: TMEM199.
Congenital disorders of glycosylation v6.11 TMEM199 Eleanor Williams commented on gene: TMEM199
Congenital disorders of glycosylation v6.11 TMEM199 Eleanor Williams Tag new-gene-name tag was added to gene: TMEM199.
White matter disorders and cerebral calcification - narrow panel v6.8 LSM7 Arina Puzriakova Added comment: Comment on publications: PMID: 39420558 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
White matter disorders and cerebral calcification - narrow panel v6.8 LSM7 Arina Puzriakova Publications for gene: LSM7 were set to https://doi.org/10.1016/j.xhgg.2021.100034
Fetal anomalies v5.80 EFCAB1 Eleanor Williams changed review comment from: Added new-gene-name tag, new approved HGNC gene symbol forEFCAB1 is CLXN; to: Added new-gene-name tag, new approved HGNC gene symbol for EFCAB1 is CLXN
Fetal anomalies v5.80 EFCAB1 Eleanor Williams commented on gene: EFCAB1
Childhood onset dystonia, chorea or related movement disorder v6.5 CCDC115 Eleanor Williams commented on gene: CCDC115
Childhood onset dystonia, chorea or related movement disorder v6.5 CCDC115 Eleanor Williams Tag new-gene-name tag was added to gene: CCDC115.
Intellectual disability v8.130 CCDC115 Eleanor Williams commented on gene: CCDC115
Intellectual disability v8.130 CCDC115 Eleanor Williams Tag new-gene-name tag was added to gene: CCDC115.
DDG2P v5.48 CCDC115 Eleanor Williams commented on gene: CCDC115
DDG2P v5.48 CCDC115 Eleanor Williams Tag new-gene-name tag was added to gene: CCDC115.
Fetal anomalies v5.80 CCDC115 Eleanor Williams commented on gene: CCDC115
Fetal anomalies v5.80 CCDC115 Eleanor Williams Tag new-gene-name tag was added to gene: CCDC115.
Intellectual disability v8.130 ZNRF3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ZNRF3.
Paediatric disorders - additional genes v6.13 ZNRF3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ZNRF3.
Likely inborn error of metabolism v7.13 CCDC115 Eleanor Williams commented on gene: CCDC115
Likely inborn error of metabolism v7.13 CCDC115 Eleanor Williams Tag new-gene-name tag was added to gene: CCDC115.
DDG2P v5.48 USP14 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: USP14.
Fetal anomalies v5.80 USP14 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: USP14.
Undiagnosed metabolic disorders v1.624 CCDC115 Eleanor Williams commented on gene: CCDC115
Undiagnosed metabolic disorders v1.624 CCDC115 Eleanor Williams Tag new-gene-name tag was added to gene: CCDC115.
Fetal anomalies v5.80 TSHZ3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: TSHZ3.
Paediatric or syndromic cardiomyopathy v6.7 TAF1A Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: TAF1A.
DDG2P v5.48 SLC12A9 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: SLC12A9.
Congenital disorders of glycosylation v6.11 CCDC115 Eleanor Williams commented on gene: CCDC115
Intellectual disability v8.130 RBBP5 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RBBP5.
DDG2P v5.48 RBBP5 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RBBP5.
Congenital disorders of glycosylation v6.11 CCDC115 Eleanor Williams Tag new-gene-name tag was added to gene: CCDC115.
DDG2P v5.48 RAB1A Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RAB1A.
Intellectual disability v8.130 PSMC5 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: PSMC5.
Fetal anomalies v5.80 PAN2 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: PAN2.
Hereditary neuropathy or pain disorder v6.163 NDC1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: NDC1.
Fetal anomalies v5.80 MYBBP1A Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: MYBBP1A.
Early onset or syndromic epilepsy v7.54 MARK2 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: MARK2.
Intellectual disability v8.130 MARK2 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: MARK2.
Hereditary neuropathy or pain disorder v6.163 ADPRHL2 Eleanor Williams commented on gene: ADPRHL2
Fetal anomalies v5.80 MAP4K4 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: MAP4K4.
Hereditary neuropathy or pain disorder v6.163 ADPRHL2 Eleanor Williams Tag new-gene-name tag was added to gene: ADPRHL2.
Intellectual disability v8.130 LRRC7 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LRRC7.
Fetal anomalies v5.80 KIF5B Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: KIF5B.
Skeletal dysplasia v7.26 KIF5B Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: KIF5B.
Fetal anomalies v5.80 KIF24 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: KIF24.
Fetal anomalies v5.80 KDM2B Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: KDM2B.
Intellectual disability v8.130 HDAC3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: HDAC3.
DDG2P v5.48 HDAC3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: HDAC3.
Fetal anomalies v5.80 GON4L Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: GON4L.
DDG2P v5.48 FEM1B Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: FEM1B.
DDG2P v5.48 EPB41L3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: EPB41L3.
DDG2P v5.48 DIP2C Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DIP2C.
Intellectual disability v8.130 DDX17 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DDX17.
DDG2P v5.48 CCT6A Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: CCT6A.
Fetal anomalies v5.80 CBY1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: CBY1.
Fetal anomalies v5.80 AMOTL1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: AMOTL1.
DDG2P v5.48 ZSCAN10 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ZSCAN10.
DDG2P v5.48 ZSCAN10 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620910).
DDG2P v5.48 ZSCAN10 Achchuthan Shanmugasundram Phenotypes for gene: ZSCAN10 were changed from ZSCAN10-related neurodevelopmental disorder with oto-facial malformations to ZSCAN10-related neurodevelopmental disorder with oto-facial malformations
Intellectual disability v8.130 WDR83OS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #621016).
Intellectual disability v8.130 WDR83OS Achchuthan Shanmugasundram Phenotypes for gene: WDR83OS were changed from complex neurodevelopmental disorder, MONDO:0100038; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with variable familial hypercholanemia, OMIM:621016
Intellectual disability v8.129 WDR83OS Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR83OS.
Fetal anomalies v5.80 WDR44 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR44.
Intellectual disability v8.129 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620851).
Intellectual disability v8.129 RNU4-2 Achchuthan Shanmugasundram Phenotypes for gene: RNU4-2 were changed from Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related to ReNU syndrome, OMIM:620851
DDG2P v5.47 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620851).
DDG2P v5.47 RNU4-2 Achchuthan Shanmugasundram Phenotypes for gene: RNU4-2 were changed from RNU4-2 related neurodevelopmental disorder with microcephaly and seizures to RNU4-2 related neurodevelopmental disorder with microcephaly and seizures
Early onset or syndromic epilepsy v7.54 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620851).
Early onset or syndromic epilepsy v7.54 RNU4-2 Achchuthan Shanmugasundram Phenotypes for gene: RNU4-2 were changed from Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related to ReNU syndrome, OMIM:620851
Severe microcephaly v7.16 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620851).
Severe microcephaly v7.16 RNU4-2 Achchuthan Shanmugasundram Phenotypes for gene: RNU4-2 were changed from Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related to ReNU syndrome, OMIM:620851
Fetal anomalies v5.80 RNU4-2 Achchuthan Shanmugasundram Tag locus-type-rna-small-nuclear tag was added to gene: RNU4-2.
Tag gene-checked tag was added to gene: RNU4-2.
Fetal anomalies v5.80 PSMF1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: PSMF1.
Intellectual disability v8.128 LINC01578 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LINC01578.
Fetal anomalies v5.80 HECTD4 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: HECTD4.
Hereditary neuropathy or pain disorder v6.163 FICD Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: FICD.
Childhood onset hereditary spastic paraplegia v7.6 FICD Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: FICD.
Fetal anomalies v5.80 EFCAB1 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: EFCAB1.
Fetal anomalies v5.80 EFCAB1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: EFCAB1.
Intellectual disability v8.128 DHRSX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #301133).
Intellectual disability v8.128 DHRSX Achchuthan Shanmugasundram Phenotypes for gene: DHRSX were changed from congenital disorder of glycosylation, MONDO:0015286; intellectual disability, MONDO:0001071 to Congenital disorder of glycosylation, type 1DD, OMIM:301133
Intellectual disability v8.127 DHRSX Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DHRSX.
Early onset or syndromic epilepsy v7.53 DHRSX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #301133).
Early onset or syndromic epilepsy v7.53 DHRSX Achchuthan Shanmugasundram Phenotypes for gene: DHRSX were changed from congenital disorder of glycosylation, MONDO:0015286; epilepsy, MONDO:0005027 to Congenital disorder of glycosylation, type 1DD, OMIM:301133
Early onset or syndromic epilepsy v7.52 DHRSX Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DHRSX.
Monogenic hearing loss v4.79 DHRSX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #301133).
Monogenic hearing loss v4.79 DHRSX Achchuthan Shanmugasundram Phenotypes for gene: DHRSX were changed from congenital disorder of glycosylation, MONDO:0015286; hearing loss disorder, MONDO:0005365 to Congenital disorder of glycosylation, type 1DD, OMIM:301133
Likely inborn error of metabolism v7.13 DHRSX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #301133).
Likely inborn error of metabolism v7.13 DHRSX Achchuthan Shanmugasundram Phenotypes for gene: DHRSX were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type 1DD, OMIM:301133
Monogenic hearing loss v4.78 DHRSX Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DHRSX.
Likely inborn error of metabolism v7.12 DHRSX Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DHRSX.
Congenital disorders of glycosylation v6.11 DHRSX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #301133).
Congenital disorders of glycosylation v6.11 DHRSX Achchuthan Shanmugasundram Phenotypes for gene: DHRSX were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type 1DD, OMIM:301133
Congenital disorders of glycosylation v6.10 DHRSX Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DHRSX.
Fetal anomalies v5.80 DAW1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DAW1.
Fetal anomalies v5.80 C16orf62 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: C16orf62.
Intellectual disability v8.127 ATXN7L3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ATXN7L3.
Fetal anomalies v5.80 AL117258.1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: AL117258.1.
Hereditary neuropathy or pain disorder v6.163 DHX9 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620988).
Hereditary neuropathy or pain disorder v6.163 DHX9 Achchuthan Shanmugasundram Phenotypes for gene: DHX9 were changed from Adult-onset axonal neuropathy; Charcot-Marie-Tooth disease, MONDO:0015626 to Intellectual developmental disorder, autosomal dominant 75, OMIM:620988
Hereditary neuropathy or pain disorder v6.162 DHX9 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: DHX9.
Intellectual disability v8.127 DHX9 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620988).
Intellectual disability v8.127 DHX9 Achchuthan Shanmugasundram Phenotypes for gene: DHX9 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Intellectual developmental disorder, autosomal dominant 75, OMIM:620988
DDG2P v5.46 DHX9 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620988).
DDG2P v5.46 DHX9 Achchuthan Shanmugasundram Phenotypes for gene: DHX9 were changed from DHX9-related neurodevelopmental disorder and Charcot-Marie-Tooth disease to DHX9-related neurodevelopmental disorder and Charcot-Marie-Tooth disease
DDG2P v5.45 DHX9 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: DHX9.
Intellectual disability v8.126 DHX9 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: DHX9.
Paediatric disorders - additional genes v6.13 HYAL2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #621063).
Paediatric disorders - additional genes v6.13 HYAL2 Achchuthan Shanmugasundram Phenotypes for gene: HYAL2 were changed from cor triatriatum; congenital cardiac malformations to Muggenthaler-Chowdhury-Chioza syndrome, OMIM:621063
Paediatric disorders - additional genes v6.12 HYAL2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: HYAL2.
Clefting v6.5 HYAL2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #621063).
Clefting v6.5 HYAL2 Achchuthan Shanmugasundram Phenotypes for gene: HYAL2 were changed from cleft lip/palate MONDO:0016044; triatrial heart MONDO:0015450 to Muggenthaler-Chowdhury-Chioza syndrome, OMIM:621063
Clefting v6.4 HYAL2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: HYAL2.
DDG2P v5.45 HYAL2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #621063).
DDG2P v5.45 HYAL2 Achchuthan Shanmugasundram Phenotypes for gene: HYAL2 were changed from HYAL2-related syndrome with cleft lip and palate and congenital cardiac anomalies to HYAL2-related syndrome with cleft lip and palate and congenital cardiac anomalies
DDG2P v5.44 HYAL2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: HYAL2.
Fetal anomalies v5.80 HYAL2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #621063).
Fetal anomalies v5.80 HYAL2 Achchuthan Shanmugasundram Phenotypes for gene: HYAL2 were changed from congenital cardiac malformations; Cleft lip and palate; cor triatriatum to Muggenthaler-Chowdhury-Chioza syndrome, OMIM:621063
Fetal anomalies v5.79 HYAL2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: HYAL2.
Familial non syndromic congenital heart disease v1.87 HYAL2 Achchuthan Shanmugasundram Phenotypes for gene: HYAL2 were changed from cor triatriatum; congenital cardiac malformations to Muggenthaler-Chowdhury-Chioza syndrome, OMIM:621063
Familial non syndromic congenital heart disease v1.86 HYAL2 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: HYAL2.
Congenital hypothyroidism v2.23 STRTS Sarah Leigh commented on Region: STRTS
Congenital hypothyroidism v2.23 STRTS Sarah Leigh Publications for Region: STRTS were set to PMID: 38714869; 15870119
Early onset or syndromic epilepsy v7.52 CTSF Sarah Leigh Added comment: Comment on publications: PMID: 39720560 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.52 CTSF Sarah Leigh Publications for gene: CTSF were set to 16508006; 39720560
Early onset or syndromic epilepsy v7.51 CTSF Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: CTSF.
Early onset or syndromic epilepsy v7.51 CTSF Sarah Leigh reviewed gene: CTSF: Rating: GREEN; Mode of pathogenicity: None; Publications: 39720560; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.51 MARK2 Arina Puzriakova Classified gene: MARK2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.51 MARK2 Arina Puzriakova Gene: mark2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.50 MARK2 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v7.50 MARK2 Arina Puzriakova Tag Q1_25_ promote_green tag was added to gene: MARK2.
Early onset or syndromic epilepsy v7.50 MARK2 Arina Puzriakova Entity copied from Intellectual disability v8.126
Early onset or syndromic epilepsy v7.50 MARK2 Arina Puzriakova gene: MARK2 was added
gene: MARK2 was added to Early onset or syndromic epilepsy. Sources: Expert Review Green,NHS GMS,Literature
Mode of inheritance for gene: MARK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MARK2 were set to 39419027; 39436150
Phenotypes for gene: MARK2 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Early onset or syndromic epilepsy v7.49 CTSF Sarah Leigh Publications for gene: CTSF were set to 16508006
Early onset or syndromic epilepsy v7.48 CTSF Sarah Leigh Phenotypes for gene: CTSF were changed from Ceroid lipofuscinosis, neuronal, 13, Kufs type, 615362 to Ceroid lipofuscinosis, neuronal, 13, Kufs type, OMIM:615362; neuronal ceroid lipofuscinosis 13, MONDO:0014147
Intellectual disability v8.126 XPA Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: XPA.
Monogenic hearing loss v4.78 XPA Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: XPA.
Monogenic hearing loss v4.78 XPA Sarah Leigh Classified gene: XPA as Amber List (moderate evidence)
Monogenic hearing loss v4.78 XPA Sarah Leigh Gene: xpa has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v4.77 XPA Sarah Leigh Mode of inheritance for gene: XPA was changed from to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v4.76 XPA Sarah Leigh Phenotypes for gene: XPA were changed from to Xeroderma pigmentosum, group A, OMIM: 278700
Monogenic hearing loss v4.75 XPA Sarah Leigh Added comment: Comment on publications: PMID: 39621777 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Monogenic hearing loss v4.75 XPA Sarah Leigh Publications for gene: XPA were set to
Intellectual disability v8.126 XPA Sarah Leigh Added comment: Comment on publications: PMID: 39621777 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.126 XPA Sarah Leigh Publications for gene: XPA were set to 26302748; 25566891; 24135642
Intellectual disability v8.125 XPA Sarah Leigh Phenotypes for gene: XPA were changed from mental retardation; progressive intellectual impariment to Xeroderma pigmentosum, group A, OMIM: 278700
Monogenic hearing loss v4.74 XPA Sarah Leigh reviewed gene: XPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 39621777; Phenotypes: Xeroderma pigmentosum, group A, OMIM: 278700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.124 XPA Sarah Leigh changed review comment from: PMID: 39621777 reports 16 XPA variants in 18 patients with Xeroderma pigmentosum, group A (OMIM:278700). Amongst the cohort, the authors were able to classify the patients into three severity groups based on the extent of their neurological abnormalities at age 10 years (8 severe, 6 intermediate and 4 mild). The severe phenotype included developmental delay and mild to profound hearing loss, was associated with terminating variants in exons 3 and 5 of XPA, which resulted in reducing the XPA protein to undetectable levels.; to: PMID: 39621777 reports 16 XPA variants in 18 patients with Xeroderma pigmentosum, group A (OMIM:278700). Amongst the cohort, the authors were able to classify the patients into three severity groups based on the extent of their neurological abnormalities at age 10 years. There were 8 severe, 6 intermediate and 4 mild patients. The severe phenotype included developmental delay and mild to profound hearing loss, and was associated with terminating variants in exons 3 and 5 of XPA, which resulting in undetectable levels of XPA protein.
Intellectual disability v8.124 XPA Sarah Leigh reviewed gene: XPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 39621777; Phenotypes: Xeroderma pigmentosum, group A, OMIM: 278700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.47 INPP4A Arina Puzriakova Entity copied from Intellectual disability v8.124
Early onset or syndromic epilepsy v7.47 INPP4A Arina Puzriakova gene: INPP4A was added
gene: INPP4A was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber
Q1_25_ promote_green tags were added to gene: INPP4A.
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678
Phenotypes for gene: INPP4A were set to Intellectual disability; Seizures
Penetrance for gene: INPP4A were set to Complete
Intellectual disability v8.124 MAG Sarah Leigh Added comment: Comment on publications: PMID: 39336794 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.124 MAG Sarah Leigh Publications for gene: MAG were set to 39336794
Intellectual disability v8.123 MAG Sarah Leigh Classified gene: MAG as Amber List (moderate evidence)
Intellectual disability v8.123 MAG Sarah Leigh Gene: mag has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.122 MAG Sarah Leigh gene: MAG was added
gene: MAG was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: MAG.
Mode of inheritance for gene: MAG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAG were set to 39336794
Phenotypes for gene: MAG were set to Spastic paraplegia 75, autosomal recessive, OMIM:616680; hereditary spastic paraplegia 75, MONDO:0014729
Review for gene: MAG was set to GREEN
Added comment: AT least six MAG variants have been associated with Spastic paraplegia 75, autosomal recessive, OMIM:616680 in at least five unrelated cases (PMID: 24482476; 26179919; 27606346; 31402626; 39336794). It would appear that intellectual disability is a common feature in cases of OMIM:616680, although this may be mild to moderate.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v6.7 ATP11A Arina Puzriakova Tag watchlist was removed from gene: ATP11A.
Inherited white matter disorders v1.184 ATP11A Arina Puzriakova Tag watchlist was removed from gene: ATP11A.
Inherited white matter disorders v1.184 ATP11A Arina Puzriakova Publications for gene: ATP11A were set to 34403372
Inherited white matter disorders v1.183 ATP11A Arina Puzriakova Phenotypes for gene: ATP11A were changed from Leukodystrophy, hypomyelinating, 24 , OMIM:619851 to Leukodystrophy, hypomyelinating, 24, OMIM:619851
White matter disorders and cerebral calcification - narrow panel v6.7 ATP11A Arina Puzriakova Phenotypes for gene: ATP11A were changed from Neurodevelopmental disorder to Leukodystrophy, hypomyelinating, 24, OMIM:619851
Inherited white matter disorders v1.182 ATP11A Arina Puzriakova Phenotypes for gene: ATP11A were changed from Neurodevelopmental disorder to Leukodystrophy, hypomyelinating, 24 , OMIM:619851
Inherited white matter disorders v1.181 ATP11A Arina Puzriakova Classified gene: ATP11A as Amber List (moderate evidence)
Inherited white matter disorders v1.181 ATP11A Arina Puzriakova Added comment: Comment on list classification: Green recommendation on GMS panel and therefore rating Green on this 100K equivalent panel for consistency,
Inherited white matter disorders v1.181 ATP11A Arina Puzriakova Gene: atp11a has been classified as Amber List (Moderate Evidence).
Inherited white matter disorders v1.180 ATP11A Arina Puzriakova edited their review of gene: ATP11A: Changed rating: GREEN
Inherited white matter disorders v1.180 ATP11A Arina Puzriakova commented on gene: ATP11A
Hereditary ataxia with onset in adulthood v7.11 FGF14_TTC Sarah Leigh commented on STR: FGF14_TTC: The name of this STR has been changed from FGF14_GAA to FGF14_TTC as FGF14 is transcribed from the reverse strand of the sequence.
The coordinates for the repeated sequence have been updated to those shown in https://stripy.org/database/FGF14. Previously, the coordinates were for the whole gene, rather than the repeated sequence.
Hereditary neuropathy or pain disorder v6.162 FGF14_TTC Sarah Leigh commented on STR: FGF14_TTC: The name of this STR has been changed from FGF14_GAA to FGF14_TTC as FGF14 is transcribed from the reverse strand of the sequence.
The coordinates for the repeated sequence have been updated to those shown in https://stripy.org/database/FGF14. Previously, the coordinates were for the whole gene, rather than the repeated sequence.
Hereditary neuropathy or pain disorder v6.162 FGF14_TTC Sarah Leigh Tag NGS Not Validated tag was added to STR: FGF14_TTC.
Hereditary ataxia with onset in adulthood v7.11 FGF14_TTC Sarah Leigh Tag NGS Not Validated tag was added to STR: FGF14_TTC.
Hereditary neuropathy or pain disorder v6.162 FGF14_TTC Sarah Leigh FGF14_GAA was changed to FGF14_TTC
GRCh38 position for FGF14_TTC was changed from 101710804-102402443 to 102161576-102161726.
Repeated Sequence for FGF14_TTC was changed from GAA to TTC.
Source Literature was removed from STR: FGF14_TTC.
Hereditary ataxia with onset in adulthood v7.11 FGF14_TTC Sarah Leigh FGF14_GAA was changed to FGF14_TTC
GRCh38 position for FGF14_TTC was changed from 101710804-102402443 to 102161576-102161726.
Repeated Sequence for FGF14_TTC was changed from GAA to TTC.
Source Literature was removed from STR: FGF14_TTC.
Fetal anomalies v5.79 CNBP_CCTG Achchuthan Shanmugasundram commented on STR: CNBP_CCTG: The repeated sequence of this STR has been updated from 'CAGG' to 'CCTG' to match the sequence on the coding strand of the gene. This update was made following NHS Genomic Medicine Service approval.
Fetal anomalies v5.79 CNBP_CCTG Achchuthan Shanmugasundram Repeated Sequence for CNBP_CCTG was changed from CAGG to CCTG.
Skeletal muscle channelopathy v3.6 CNBP_CCTG Achchuthan Shanmugasundram commented on STR: CNBP_CCTG: The repeated sequence of this STR has been updated from 'CAGG' to 'CCTG' to match the sequence on the coding strand of the gene. This update was made following NHS Genomic Medicine Service approval.
Skeletal Muscle Channelopathies v1.47 CNBP_CCTG Achchuthan Shanmugasundram changed review comment from: The repeated sequence of this STR has been updated from 'CAGG' to 'CCTG' to match the sequence on the coding strand of the gene.; to: The repeated sequence of this STR has been updated from 'CAGG' to 'CCTG' to match the sequence on the coding strand of the gene. This update was made following NHS Genomic Medicine Service approval.
Skeletal Muscle Channelopathies v1.47 CNBP_CCTG Achchuthan Shanmugasundram commented on STR: CNBP_CCTG
Distal myopathies v6.3 CNBP_CCTG Achchuthan Shanmugasundram commented on STR: CNBP_CCTG: The repeated sequence of this STR has been updated from 'CAGG' to 'CCTG' to match the sequence on the coding strand of the gene. This update was made following NHS Genomic Medicine Service approval.
Skeletal muscle channelopathy v3.6 CNBP_CCTG Achchuthan Shanmugasundram Repeated Sequence for CNBP_CCTG was changed from CAGG to CCTG.
Distal myopathies v6.3 CNBP_CCTG Achchuthan Shanmugasundram Repeated Sequence for CNBP_CCTG was changed from CAGG to CCTG.
Skeletal Muscle Channelopathies v1.47 CNBP_CCTG Achchuthan Shanmugasundram Repeated Sequence for CNBP_CCTG was changed from CAGG to CCTG.
Congenital myopathy v5.15 GFER Achchuthan Shanmugasundram Classified gene: GFER as Green List (high evidence)
Congenital myopathy v5.15 GFER Achchuthan Shanmugasundram Gene: gfer has been classified as Green List (High Evidence).
Congenital myopathy v5.14 GFER Achchuthan Shanmugasundram Tag to_be_confirmed_NHSE was removed from gene: GFER.
Congenital myopathy v5.14 GFER Achchuthan Shanmugasundram edited their review of gene: GFER: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v8.121 CCDC88A Arina Puzriakova Publications for gene: CCDC88A were set to 26917597; 30392057; 37798908; 39334473
Intellectual disability v8.120 AFF3_GGC Sarah Leigh AFF3_GCC was changed to AFF3_GGC
Repeated Sequence for AFF3_GGC was changed from GCC to GGC.
Congenital hypothyroidism v2.22 STRTS Nadia Schoenmakers reviewed Region: STRTS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38714869, 38714868; Phenotypes: congenital hypothyroidism, subclinical hypothyroidism, TSH Resistance (RTSH), multi nodular goitre; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v8.119 LINC01578 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotype in OMIM (MIM #621012), but not yet in Gene2Phenotype.
Intellectual disability v8.119 LINC01578 Achchuthan Shanmugasundram Phenotypes for gene: LINC01578 were changed from Neurodevelopmental disorder, MONDO:0700092, CHASERR-related to Neurodevelopmental disorder with dysmorphic facies, absent speech and ambulation, and brain abnormalities, OMIM:621012
Intellectual disability v8.118 LINC01578 Achchuthan Shanmugasundram Tag locus-type-rna-long-non-coding tag was added to gene: LINC01578.
Congenital hypothyroidism v2.22 STRTS Adam Gunning Region: STRTS was added
Region: STRTS was added to Congenital hypothyroidism. Sources: Literature,NHS GMS
Mode of inheritance for Region: STRTS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for Region: STRTS were set to PMID: 38714869; 15870119
Phenotypes for Region: STRTS were set to Congenital hypothyroidism; Small thyroid (in children); Multinodular goitre (with age, if untreated); Elevated serum TSH
Penetrance for Region: STRTS were set to Complete
Review for Region: STRTS was set to GREEN
Added comment: Sources: Literature, NHS GMS
Familial hypoparathyroidism v2.18 STX16 Eleanor Williams changed review comment from: The rating of this gene has was initially changed to green (but not in the signed off version of the panel) but after further review it has been decided to keep it as amber. GLH review notes: STX16 deletions are associated with pseudohypoparathroidism (1b). Clinically this means hypocalcaemia but PTH levels are elevated – which is the normal response to low serum calcium (hence the pseudo and indicating defective response to PTH levels rather than defective PTH production as in hypoparathyroidism ).

R153 Familial hypoparathyroidism testing criteria are: Non-syndromic hypoparathyroidism with low calcium levels and low or inappropriately normal serum PTH, with no detectable cause. Clinically R153 requires hypocalcaemia and low PTH levels (/ inappropriately normal in ADH) due to defective PTH production in the main) - so patients with STX16 wont clinically fulfil R153 test criteria.

following NHS Genomic Medicine Service approval.; to: The rating of this gene has was initially changed to green (but not in the signed off version of the panel) but after further review it has been decided to keep it as amber (see review by Treena Cranston) . The clinical phenotype of pseudohypoparathroidism 1b does not fit with the testing criteria of the panel: R153 requires hypocalcaemia and low PTH levels (/ inappropriately normal in ADH) due to defective PTH production in the main) - so patients with STX16 wont clinically fulfil R153 test criteria.

Therefore this gene remains amber following NHS Genomic Medicine Service review.
Familial hypoparathyroidism v2.18 STX16 Eleanor Williams edited their review of gene: STX16: Changed rating: AMBER
Familial hypoparathyroidism v2.18 STX16 Eleanor Williams changed review comment from: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; to: The rating of this gene has was initially changed to green (but not in the signed off version of the panel) but after further review it has been decided to keep it as amber. GLH review notes: STX16 deletions are associated with pseudohypoparathroidism (1b). Clinically this means hypocalcaemia but PTH levels are elevated – which is the normal response to low serum calcium (hence the pseudo and indicating defective response to PTH levels rather than defective PTH production as in hypoparathyroidism ).

R153 Familial hypoparathyroidism testing criteria are: Non-syndromic hypoparathyroidism with low calcium levels and low or inappropriately normal serum PTH, with no detectable cause. Clinically R153 requires hypocalcaemia and low PTH levels (/ inappropriately normal in ADH) due to defective PTH production in the main) - so patients with STX16 wont clinically fulfil R153 test criteria.

following NHS Genomic Medicine Service approval.
Monogenic hearing loss v4.74 HGF Achchuthan Shanmugasundram changed review comment from: Three different biallelic variants in HGF gene were identified in more than 60 unrelated families reported in PMIDs:19576567 and 30303587 with profound prelingual deafness. There is also mouse model available in support of the disease association. These evidence suggest that the gene should be promoted to green rating in the next GMS review. However, the previous review from Eleanor Williams note it was decided to rate this gene to amber with the 'watchlist' tag after review with the GMS hearing specialist test group in a Webex on 2019-02-13 and consultation with the Genomics England clinical team. So, I am requesting expert review from the GMS to decide whether this gene can be promoted to green rating now.; to: Three different biallelic variants in HGF gene were identified in more than 60 unrelated families reported in PMIDs:19576567 and 30303587 with profound prelingual deafness. There is also mouse model available in support of the disease association. These evidence suggest that the gene should be promoted to green rating in the next GMS review. However, the previous review from Eleanor Williams note that it was decided to rate this gene to amber with the 'watchlist' tag after review with the GMS hearing specialist test group in a Webex on 2019-02-13 and consultation with the Genomics England clinical team. So, I am requesting expert review from the GMS to decide whether this gene can be promoted to green rating now.
Familial hypoparathyroidism v2.18 STX16 Achchuthan Shanmugasundram Classified gene: STX16 as Amber List (moderate evidence)
Familial hypoparathyroidism v2.18 STX16 Achchuthan Shanmugasundram Gene: stx16 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.118 TDP1 Sarah Leigh Classified gene: TDP1 as Amber List (moderate evidence)
Intellectual disability v8.118 TDP1 Sarah Leigh Added comment: Comment on list classification: This gene remains amber, as there are only two disease associated variants have been reported (PMID: 12244316;31182267;39576382).
Intellectual disability v8.118 TDP1 Sarah Leigh Gene: tdp1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.117 TDP1 Sarah Leigh Added comment: Comment on publications: PMID: 39576382 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.117 TDP1 Sarah Leigh Publications for gene: TDP1 were set to 12244316; 31182267; 39576382
Hereditary neuropathy or pain disorder v6.161 TDP1 Sarah Leigh Added comment: Comment on publications: PMID: 39576382 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Hereditary neuropathy or pain disorder v6.161 TDP1 Sarah Leigh Publications for gene: TDP1 were set to 12244316; 31182267; 39576382
Hereditary neuropathy or pain disorder v6.160 TDP1 Sarah Leigh Classified gene: TDP1 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v6.160 TDP1 Sarah Leigh Added comment: Comment on list classification: This gene remains amber, as there are only two disease associated variants have been reported (PMID: 12244316;31182267;39576382)
Hereditary neuropathy or pain disorder v6.160 TDP1 Sarah Leigh Gene: tdp1 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v6.159 TDP1 Sarah Leigh Publications for gene: TDP1 were set to 12244316; 31182267; 39576382
Intellectual disability v8.116 TDP1 Sarah Leigh Entity copied from Hereditary neuropathy or pain disorder v6.158
Intellectual disability v8.116 TDP1 Sarah Leigh gene: TDP1 was added
gene: TDP1 was added to Intellectual disability. Sources: Expert Review Amber,South West GLH,UKGTN,Emory Genetics Laboratory,Expert list,NHS GMS
founder-effect tags were added to gene: TDP1.
Mode of inheritance for gene: TDP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDP1 were set to 12244316; 31182267; 39576382
Phenotypes for gene: TDP1 were set to ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250
Hereditary neuropathy or pain disorder v6.157 TDP1 Sarah Leigh reviewed gene: TDP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39576382; Phenotypes: ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, MONDO:0011801; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.157 TDP1 Sarah Leigh Publications for gene: TDP1 were set to 12244316; 31182267
Intellectual disability v8.115 PPP2R5C Sarah Leigh Publications for gene: PPP2R5C were set to 25972378; 39500882; 39978342
Early onset or syndromic epilepsy v7.46 PPP2R5C Sarah Leigh Classified gene: PPP2R5C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.46 PPP2R5C Sarah Leigh Gene: ppp2r5c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.45 PPP2R5C Sarah Leigh Added comment: Comment on publications: PMID: 39696819 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.45 PPP2R5C Sarah Leigh Publications for gene: PPP2R5C were set to 25972378; 39696819; 39978342
Early onset or syndromic epilepsy v7.44 PPP2R5C Sarah Leigh edited their review of gene: PPP2R5C: Changed publications to: 25972378, 39696819, 39978342
Intellectual disability v8.114 PPP2R5C Sarah Leigh edited their review of gene: PPP2R5C: Changed publications to: 25972378, 39696819, 39978342
Intellectual disability v8.114 PPP2R5C Sarah Leigh changed review comment from: PMIDs 25972378; 39500882; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature; to: PMIDs 25972378; 39696819; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39696819 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Early onset or syndromic epilepsy v7.44 PPP2R5C Sarah Leigh changed review comment from: PMIDs 25972378; 39696819; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature; to: PMIDs 25972378; 39696819; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39696819 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature
Early onset or syndromic epilepsy v7.44 PPP2R5C Sarah Leigh changed review comment from: PMIDs 25972378; 39500882; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature; to: PMIDs 25972378; 39696819; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature
Early onset or syndromic epilepsy v7.44 PPP2R5C Sarah Leigh Publications for gene: PPP2R5C were set to 25972378; 39500882; 39978342
Intellectual disability v8.114 PPP2R5C Sarah Leigh Added comment: Comment on publications: PMID: 39696819 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.114 PPP2R5C Sarah Leigh Publications for gene: PPP2R5C were set to 25972378; 39500882; 39978342
Intellectual disability v8.113 PPP2R5C Sarah Leigh Classified gene: PPP2R5C as Amber List (moderate evidence)
Intellectual disability v8.113 PPP2R5C Sarah Leigh Gene: ppp2r5c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.43 PPP2R5C Sarah Leigh gene: PPP2R5C was added
gene: PPP2R5C was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_25_ promote_green tags were added to gene: PPP2R5C.
Mode of inheritance for gene: PPP2R5C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP2R5C were set to 25972378; 39500882; 39978342
Phenotypes for gene: PPP2R5C were set to neurodevelopmental disorder
Review for gene: PPP2R5C was set to GREEN
Added comment: PMIDs 25972378; 39500882; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature
Intellectual disability v8.112 PPP2R5C Sarah Leigh gene: PPP2R5C was added
gene: PPP2R5C was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: PPP2R5C.
Mode of inheritance for gene: PPP2R5C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP2R5C were set to 25972378; 39500882; 39978342
Phenotypes for gene: PPP2R5C were set to neurodevelopmental disorder
Review for gene: PPP2R5C was set to GREEN
Added comment: PMIDs 25972378; 39500882; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature
Intellectual disability v8.111 GON4L Sarah Leigh Added comment: Comment on publications: PMID: 39500882 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.111 GON4L Sarah Leigh Publications for gene: GON4L were set to 21937992; 26350204; 24896178; 39500882
Intellectual disability v8.110 GON4L Sarah Leigh Phenotypes for gene: GON4L were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to prenatal-onset growth impairment and developmental delay
Intellectual disability v8.110 GON4L Sarah Leigh Classified gene: GON4L as Amber List (moderate evidence)
Intellectual disability v8.110 GON4L Sarah Leigh Added comment: Comment on list classification: This gene is rated as amber, as only mild intellectual disability has been associated with GON4L variants (PMID: 39500882).
Intellectual disability v8.110 GON4L Sarah Leigh Gene: gon4l has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.109 GON4L Sarah Leigh edited their review of gene: GON4L: Added comment: PMID: 39500882 reports two consanguineous families where children who are homozygous for terminating GON4L variants, have prenatal-onset growth impairment, developmental delay, and mild intellectual disability. The unaffected parents of both children and an unaffected sibling were heterozygous for the GON4L variants identified. Microcephaly was reported in the affected cases, however, it was now severe. Functional studies in gon4lb-knockout and knockdown zebrafish
revealed distinct morphological and size abnormalities, which were reminiscent of the human phenotype. Human wild type GON4L mRNA was able to rescue the craniofacial cartilage phenotypic in zebrafish larvae PMID: 39500882.; Changed rating: AMBER; Changed publications to: 39500882; Changed phenotypes to: prenatal-onset growth impairment and developmental delay; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy v4.21 MT-TI Eleanor Williams changed review comment from: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval. However, reviewers note that only the m.4300A>G variant should be looked at.; to: The rating of this gene was initially updated to green following NHS Genomic Medicine Service approval, but after later review it was demoted to amber again before the panel was signed off for GMS use, with the comment that it would be better to be analysed through the WGS panel R135 Paediatric or syndromic cardiomyopathy. Reviewers also noted that only the m.4300A>G variant should be looked at.
Deafness and congenital structural abnormalities v1.27 KIAA0391 Bill Newman gene: KIAA0391 was added
gene: KIAA0391 was added to Deafness and congenital structural abnormalities. Sources: Literature
Mode of inheritance for gene: KIAA0391 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0391 were set to PMID:34715011; 37558808
Phenotypes for gene: KIAA0391 were set to Sensorineural hearing loss; primary ovarian insufficiency; leukodystrophy
Penetrance for gene: KIAA0391 were set to Complete
Review for gene: KIAA0391 was set to GREEN
Added comment: Note this gene should be called PRORP (also known as MRPP3)

Biallelic hylomorphic missense variants in the metallonuclease domain associated with this phenotype
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.40 ACTN2 Cassandra Smith reviewed gene: ACTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38311799; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Deafness and congenital structural abnormalities v1.27 DAP3 Bill Newman gene: DAP3 was added
gene: DAP3 was added to Deafness and congenital structural abnormalities. Sources: Literature
Mode of inheritance for gene: DAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAP3 were set to PMID:39701103
Phenotypes for gene: DAP3 were set to Sensorineural hearing loss; primary ovarian insufficiency; lactic acidosis; intellectual disability
Penetrance for gene: DAP3 were set to Complete
Mode of pathogenicity for gene: DAP3 was set to Other
Review for gene: DAP3 was set to GREEN
Added comment: This is a new description of hypomorphic biallelic variants resulting in a multi system disorder including SNHL
Biallelic LoF variants are unlikely to viable
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v3.25 CFAP74 Steven Cowman reviewed gene: CFAP74: Rating: GREEN; Mode of pathogenicity: None; Publications: 32555313, 36047773, 39362668; Phenotypes: Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v4.74 HGF Achchuthan Shanmugasundram Phenotypes for gene: HGF were changed from Nonsyndromic Hearing Loss, Mixed; Deafness, autosomal recessive 39, 608265 to Deafness, autosomal recessive 39, OMIM:608265
Monogenic hearing loss v4.73 HGF Achchuthan Shanmugasundram Publications for gene: HGF were set to PMID:11343646; 11564764; 11565020; 12574630; 1386343; 14556002; 14691191; 1531136; 1535333; 15545993; 17467663; 1824873; 1831266; 1837534; 19188684; 19576567; 2142751; 21988987; 21988988; 22763439; 22763448; 2528952; 2531289; 3276728; 7624797; 7854452; 7854453; 8804995; 8898205; 19576567; 27610647
Monogenic hearing loss v4.72 HGF Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: HGF.
Tag Q1_25_ expert_review tag was added to gene: HGF.
Monogenic hearing loss v4.72 HGF Achchuthan Shanmugasundram reviewed gene: HGF: Rating: GREEN; Mode of pathogenicity: None; Publications: 19576567, 30303587; Phenotypes: Deafness, autosomal recessive 39, OMIM:608265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial hypoparathyroidism v2.17 STX16 Treena Cranston reviewed gene: STX16: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v8.109 GON4L Sarah Leigh Publications for gene: GON4L were set to 21937992
Intellectual disability v8.108 PNPLA8 Sarah Leigh Added comment: Comment on publications: PMID: 39082157 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.108 PNPLA8 Sarah Leigh Publications for gene: PNPLA8 were set to 39082157
Early onset or syndromic epilepsy v7.42 PNPLA8 Sarah Leigh Added comment: Comment on publications: PMID: 39082157 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.42 PNPLA8 Sarah Leigh Publications for gene: PNPLA8 were set to 39082157
Intellectual disability v8.107 PNPLA8 Sarah Leigh Classified gene: PNPLA8 as Amber List (moderate evidence)
Intellectual disability v8.107 PNPLA8 Sarah Leigh Gene: pnpla8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.41 PNPLA8 Sarah Leigh Classified gene: PNPLA8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.41 PNPLA8 Sarah Leigh Gene: pnpla8 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v7.15 PNPLA8 Sarah Leigh Added comment: Comment on publications: PMID: 39082157 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Severe microcephaly v7.15 PNPLA8 Sarah Leigh Publications for gene: PNPLA8 were set to 39082157
Severe microcephaly v7.14 PNPLA8 Sarah Leigh Classified gene: PNPLA8 as Amber List (moderate evidence)
Severe microcephaly v7.14 PNPLA8 Sarah Leigh Gene: pnpla8 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v7.13 PNPLA8 Sarah Leigh gene: PNPLA8 was added
gene: PNPLA8 was added to Severe microcephaly. Sources: Literature
Q1_25_ promote_green tags were added to gene: PNPLA8.
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to 39082157
Phenotypes for gene: PNPLA8 were set to ?Mitochondrial myopathy with lactic acidosis, OMIM:251950; mitochondrial myopathy-lactic acidosis-deafness syndrome MONDO:0016825
Review for gene: PNPLA8 was set to GREEN
Added comment: Biallelic PNPLA8 variants have previously been associated with Mitochondrial myopathy with lactic acidosis, (OMIM:251950). PMID: 39082157 reports a study were microcephaly, global delay and seizures are associated with biallelic PNPLA8 variants. Amongst the unrelated individuals studied, 8/11 had severe microcephaly, 9/11 had epileptic seizures and 8/11 had severe global delay and intellectual disability where it could be measured, 3/11 cases died in childhood and affected siblings (but not genotyped) had died in two other families. Using cerebral organoids generated from human induced pluripotent stem cells, the authors were able to assert that the loss of PNPLA8 led to
developmental defects by reducing the number of basal radial glial cells and upper-layer neurons (PMID: 39082157).
Sources: Literature
Early onset or syndromic epilepsy v7.40 PNPLA8 Sarah Leigh gene: PNPLA8 was added
gene: PNPLA8 was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_25_ promote_green tags were added to gene: PNPLA8.
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to 39082157
Phenotypes for gene: PNPLA8 were set to ?Mitochondrial myopathy with lactic acidosis, OMIM:251950; mitochondrial myopathy-lactic acidosis-deafness syndrome MONDO:0016825
Review for gene: PNPLA8 was set to GREEN
Added comment: Biallelic PNPLA8 variants have previously been associated with Mitochondrial myopathy with lactic acidosis, (OMIM:251950). PMID: 39082157 reports a study were microcephaly, global delay and seizures are associated with biallelic PNPLA8 variants. Amongst the unrelated individuals studied, 8/11 had severe microcephaly, 9/11 had epileptic seizures and 8/11 had severe global delay and intellectual disability where it could be measured, 3/11 cases died in childhood and affected siblings (but not genotyped) had died in two other families. Using cerebral organoids generated from human induced pluripotent stem cells, the authors were able to assert that the loss of PNPLA8 led to
developmental defects by reducing the number of basal radial glial cells and upper-layer neurons (PMID: 39082157).
Sources: Literature
Intellectual disability v8.106 PNPLA8 Sarah Leigh gene: PNPLA8 was added
gene: PNPLA8 was added to Intellectual disability. Sources: Literature
Q1_25_ promote_green tags were added to gene: PNPLA8.
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to 39082157
Phenotypes for gene: PNPLA8 were set to ?Mitochondrial myopathy with lactic acidosis, OMIM:251950; mitochondrial myopathy-lactic acidosis-deafness syndrome MONDO:0016825
Review for gene: PNPLA8 was set to GREEN
Added comment: Biallelic PNPLA8 variants have previously been associated with Mitochondrial myopathy with lactic acidosis, (OMIM:251950). PMID: 39082157 reports a study were microcephaly, global delay and seizures are associated with biallelic PNPLA8 variants. Amongst the unrelated individuals studied, 8/11 had severe microcephaly, 9/11 had epileptic seizures and 8/11 had severe global delay and intellectual disability where it could be measured, 3/11 cases died in childhood and affected siblings (but not genotyped) had died in two other families. Using cerebral organoids generated from human induced pluripotent stem cells, the authors were able to assert that the loss of PNPLA8 led to
developmental defects by reducing the number of basal radial glial cells and upper-layer neurons (PMID: 39082157).
Sources: Literature
Hypogonadotropic hypogonadism (GMS) v3.25 RNF216 Sarah Leigh Classified gene: RNF216 as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v3.25 RNF216 Sarah Leigh Gene: rnf216 has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v3.24 RNF216 Sarah Leigh Added comment: Comment on publications: PMID: 39444518 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Hypogonadotropic hypogonadism (GMS) v3.24 RNF216 Sarah Leigh Publications for gene: RNF216 were set to 39444518; 23656588; 25841028
Hypogonadotropic hypogonadism (GMS) v3.23 RNF216 Sarah Leigh gene: RNF216 was added
gene: RNF216 was added to Hypogonadotropic hypogonadism (GMS). Sources: Literature
Q1_25_ promote_green tags were added to gene: RNF216.
Mode of inheritance for gene: RNF216 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF216 were set to 39444518; 23656588; 25841028
Phenotypes for gene: RNF216 were set to Cerebellar ataxia and hypogonadotropic hypogonadism, OMIM:212840; cerebellar ataxia-hypogonadism syndrome, MONDO:0008935
Review for gene: RNF216 was set to GREEN
Added comment: RNF216 variants are associated with Cerebellar ataxia and hypogonadotropic hypogonadism (OMIM:212840). At least seven RNF216 variants have been reported in five unrelated cases of OMIM:212840 (PMID: 39444518; 23656588;25841028).
Sources: Literature
Intellectual disability v8.105 PLEKHG1 Sarah Leigh Added comment: Comment on publications: PMID: 39202455 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability v8.105 PLEKHG1 Sarah Leigh Publications for gene: PLEKHG1 were set to 39202455; 30659137
Intellectual disability v8.104 PLEKHG1 Sarah Leigh gene: PLEKHG1 was added
gene: PLEKHG1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLEKHG1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PLEKHG1 were set to 39202455; 30659137
Phenotypes for gene: PLEKHG1 were set to Spastic diplegia and psychomotor developmental delay
Review for gene: PLEKHG1 was set to RED
Added comment: PMID: 39202455 reports a de novo heterozygous PLEKHG1 variant (NM_001029884.3 c.370A>G, p.Thr124Ala) in a child with spastic diplegia and psychomotor developmental delay. The child also had cystic fibrosis, due causative CFTR variants inherited from the parents.
A genome-wide association meta-analysis has previously associated the PLEKHG1 locus with white matter hyperintensities (PMID: 30659137).
Sources: Literature
Skeletal dysplasia v7.26 ISCA-37447-Loss Arina Puzriakova edited their review of Region: ISCA-37447-Loss: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Intellectual disability v8.103 ISCA-37447-Loss Arina Puzriakova Classified Region: ISCA-37447-Loss as Green List (high evidence)
Intellectual disability v8.103 ISCA-37447-Loss Arina Puzriakova Region: isca-37447-loss has been classified as Green List (High Evidence).
Skeletal dysplasia v7.26 ISCA-37447-Loss Arina Puzriakova Classified Region: ISCA-37447-Loss as Green List (high evidence)
Skeletal dysplasia v7.26 ISCA-37447-Loss Arina Puzriakova Region: isca-37447-loss has been classified as Green List (High Evidence).
Skeletal dysplasia v7.25 ISCA-37447-Loss Arina Puzriakova Added comment: Comment on mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) has been agreed for the R104 Skeletal dysplasia panel as only Kagami-Ogata syndrome includes skeletal abnormalities.
Skeletal dysplasia v7.25 ISCA-37447-Loss Arina Puzriakova Mode of inheritance for Region: ISCA-37447-Loss was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Intellectual disability v8.102 ISCA-37447-Loss Arina Puzriakova Added comment: Comment on mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown has been agreed for the R29 Intellectual disability panel. This would capture both imprinting patterns where there is clinical overlap between Kagami-Ogata and Temple syndrome which are both relevant to this panel.

These disorders are suitable for R27 Paediatric disorders and R69 Hypotonic infant super panels (included via R29)
Intellectual disability v8.102 ISCA-37447-Loss Arina Puzriakova Mode of inheritance for Region: ISCA-37447-Loss was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v8.101 ARHGEF40 Sarah Leigh Tag watchlist tag was added to gene: ARHGEF40.
Skeletal dysplasia v7.24 ISCA-37447-Loss Arina Puzriakova Region: ISCA-37447-Loss was added
Region: ISCA-37447-Loss was added to Skeletal dysplasia. Sources: ClinGen
Mode of inheritance for Region: ISCA-37447-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37447-Loss were set to 20585555; 24801763; 27406249; 33579810; 18176563; 28640239
Phenotypes for Region: ISCA-37447-Loss were set to Kagami-Ogata syndrome, OMIM:608149; Temple syndrome, OMIM:616222
Review for Region: ISCA-37447-Loss was set to GREEN
Added comment: Multiple unrelated cases curated in ClinGen - sufficient evidence to add this region (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37447)

DLK1-MEG3 Intergenic Region includes the paternally expressed DLK1 gene, the 2 differentially methylated regions (DMRs) DLK1/MEG3:IG-DMR and MEG3:TSS-DMR, and the 5' end of the maternally expressed gene MEG3 (4 exons).

The phenotype depends on the parental origin: Kagami Ogata syndrome/KOS (maternally derived imprinting) or Temple syndrome/TS (paternally derived imprinting)

Kagami-Ogata syndrome is characterized by typical facial features, skeletal abnormalities (including ""coat-hanger ribs"", and bell-shaped thorax), abdominal wall defects, and developmental delay.

Temple syndrome is a less specific phenotype including intrauterine and postnatal growth restriction, hypotonia, feeding difficulties in infancy, truncal obesity, and small feet and hands.
Sources: ClinGen
Intellectual disability v8.101 ISCA-37447-Loss Arina Puzriakova Region: ISCA-37447-Loss was added
Region: ISCA-37447-Loss was added to Intellectual disability. Sources: ClinGen
Mode of inheritance for Region: ISCA-37447-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37447-Loss were set to 20585555; 24801763; 27406249; 33579810; 18176563; 28640239
Phenotypes for Region: ISCA-37447-Loss were set to Kagami-Ogata syndrome, OMIM:608149; Temple syndrome, OMIM:616222
Review for Region: ISCA-37447-Loss was set to GREEN
Added comment: Multiple unrelated cases curated in ClinGen - sufficient evidence to add this region (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37447)

DLK1-MEG3 Intergenic Region includes the paternally expressed DLK1 gene, the 2 differentially methylated regions (DMRs) DLK1/MEG3:IG-DMR and MEG3:TSS-DMR, and the 5' end of the maternally expressed gene MEG3 (4 exons).

The phenotype depends on the parental origin: Kagami Ogata syndrome/KOS (maternally derived imprinting) or Temple syndrome/TS (paternally derived imprinting)

Kagami-Ogata syndrome is characterized by typical facial features, skeletal abnormalities (including ""coat-hanger ribs"", and bell-shaped thorax), abdominal wall defects, and developmental delay.

Temple syndrome is a less specific phenotype including intrauterine and postnatal growth restriction, hypotonia, feeding difficulties in infancy, truncal obesity, and small feet and hands.
Sources: ClinGen
Skeletal dysplasia v7.23 EXOC6B Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: EXOC6B.
Skeletal dysplasia v7.23 TOMM7 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: TOMM7.
Tag Q3_24_NHS_review was removed from gene: TOMM7.
Early onset or syndromic epilepsy v7.39 TRPM7 Achchuthan Shanmugasundram Tag Q1_23_promote_green was removed from gene: TRPM7.
Tag Q1_25_ promote_green tag was added to gene: TRPM7.
Likely inborn error of metabolism v7.12 TRPM7 Achchuthan Shanmugasundram Tag Q1_23_promote_green was removed from gene: TRPM7.
Tag Q1_25_ promote_green tag was added to gene: TRPM7.
Fetal anomalies v5.78 ESAM Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: ESAM.
Tag Q4_23_NHS_review was removed from gene: ESAM.
Intellectual disability v8.100 ATP11A Sarah Leigh Publications for gene: ATP11A were set to 34403372; 39432785
Intellectual disability v8.99 ATP11A Sarah Leigh Added comment: Comment on publications: PMID: 39432785 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Intellectual disability v8.99 ATP11A Sarah Leigh Publications for gene: ATP11A were set to 34403372; 39432785
Intellectual disability v8.98 ATP11A Sarah Leigh reviewed gene: ATP11A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
White matter disorders and cerebral calcification - narrow panel v6.6 ATP11A Sarah Leigh Added comment: Comment on publications: PMID: 39432785 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
White matter disorders and cerebral calcification - narrow panel v6.6 ATP11A Sarah Leigh Publications for gene: ATP11A were set to 34403372; 39432785
White matter disorders and cerebral calcification - narrow panel v6.5 ATP11A Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: ATP11A.
White matter disorders and cerebral calcification - narrow panel v6.5 ATP11A Sarah Leigh reviewed gene: ATP11A: Rating: GREEN; Mode of pathogenicity: None; Publications: 34403372, 39432785; Phenotypes: Leukodystrophy, hypomyelinating, 24, OMIM:619851, leukodystrophy, hypomyelinating, 24 MONDO:0859242; Mode of inheritance: None
Fetal anomalies v5.78 CNBP_CCTG Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from STR: CNBP_CCTG.
Fetal anomalies v5.78 CNBP_CCTG Achchuthan Shanmugasundram edited their review of STR: CNBP_CCTG: Changed rating: AMBER
Intellectual disability v8.98 ATP11A Sarah Leigh Publications for gene: ATP11A were set to 34403372
White matter disorders and cerebral calcification - narrow panel v6.5 ATP11A Sarah Leigh Publications for gene: ATP11A were set to 34403372
Fetal anomalies v5.78 CNBP_CCTG Achchuthan Shanmugasundram commented on STR: CNBP_CCTG
Fetal anomalies v5.78 KIF26A Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: KIF26A.
Tag Q1_25_ promote_green was removed from gene: KIF26A.
Fetal anomalies v5.78 DAW1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: DAW1.
Tag Q1_25_ promote_green was removed from gene: DAW1.
Fetal anomalies v5.78 ZRSR2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: ZRSR2.
Tag Q1_25_ promote_green was removed from gene: ZRSR2.
Fetal anomalies v5.78 ZFX Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: ZFX.
Tag Q1_25_ promote_green was removed from gene: ZFX.
Fetal anomalies v5.78 WDR44 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: WDR44.
Tag Q1_25_ promote_green was removed from gene: WDR44.
Fetal anomalies v5.78 WBP4 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: WBP4.
Tag Q1_25_ promote_green was removed from gene: WBP4.
Fetal anomalies v5.78 WASHC5 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: WASHC5.
Tag Q1_25_ promote_green was removed from gene: WASHC5.
Fetal anomalies v5.78 USP14 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: USP14.
Fetal anomalies v5.78 UFSP2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: UFSP2.
Tag Q1_25_ promote_green was removed from gene: UFSP2.
Fetal anomalies v5.78 U2AF2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: U2AF2.
Tag Q1_25_ promote_green was removed from gene: U2AF2.
Fetal anomalies v5.78 TSHZ3 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: TSHZ3.
Tag Q1_25_ promote_green was removed from gene: TSHZ3.
Fetal anomalies v5.78 TRIT1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: TRIT1.
Tag Q1_25_ promote_green was removed from gene: TRIT1.
Fetal anomalies v5.78 TONSL Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: TONSL.
Tag Q1_25_ promote_green was removed from gene: TONSL.
Fetal anomalies v5.78 TOGARAM1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: TOGARAM1.
Tag Q1_25_ promote_green was removed from gene: TOGARAM1.
Fetal anomalies v5.78 THSD1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: THSD1.
Tag Q1_25_ promote_green was removed from gene: THSD1.
Fetal anomalies v5.78 TBR1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: TBR1.
Tag Q1_25_ promote_green was removed from gene: TBR1.
Fetal anomalies v5.78 TAF8 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: TAF8.
Tag Q1_25_ promote_green was removed from gene: TAF8.
Fetal anomalies v5.78 SNF8 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: SNF8.
Tag Q1_23_promote_green was removed from gene: SNF8.
Fetal anomalies v5.78 SNAP25 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: SNAP25.
Tag Q1_25_ promote_green was removed from gene: SNAP25.
Fetal anomalies v5.78 SMPD1 Achchuthan Shanmugasundram Tag Q1_25_ demote_amber was removed from gene: SMPD1.
Tag Q1_25_ NHS_review was removed from gene: SMPD1.
Fetal anomalies v5.78 SLC4A10 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: SLC4A10.
Tag Q1_25_ promote_green was removed from gene: SLC4A10.
Fetal anomalies v5.78 SLC34A1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: SLC34A1.
Tag Q1_25_ promote_green was removed from gene: SLC34A1.
Fetal anomalies v5.78 SLC25A4 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: SLC25A4.
Tag Q1_25_ promote_green was removed from gene: SLC25A4.
Fetal anomalies v5.78 SETD1A Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: SETD1A.
Tag Q1_25_ promote_green was removed from gene: SETD1A.
Fetal anomalies v5.78 SCYL2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: SCYL2.
Tag Q1_25_ promote_green was removed from gene: SCYL2.
Fetal anomalies v5.78 SASS6 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: SASS6.
Tag Q1_25_ promote_green was removed from gene: SASS6.
Fetal anomalies v5.78 RSPRY1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: RSPRY1.
Tag Q1_25_ promote_green was removed from gene: RSPRY1.
Fetal anomalies v5.78 RSPO2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: RSPO2.
Tag Q1_25_ promote_green was removed from gene: RSPO2.
Fetal anomalies v5.78 RRAS Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: RRAS.
Tag Q1_25_ promote_green was removed from gene: RRAS.
Fetal anomalies v5.78 RRAGC Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: RRAGC.
Tag Q1_25_ promote_green was removed from gene: RRAGC.
Fetal anomalies v5.78 RPL13 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: RPL13.
Tag Q1_25_ promote_green was removed from gene: RPL13.
Fetal anomalies v5.78 ROBO1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: ROBO1.
Tag Q1_24_MOI was removed from gene: ROBO1.
Fetal anomalies v5.78 RNU4-2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: RNU4-2.
Tag Q1_25_ promote_green was removed from gene: RNU4-2.
Fetal anomalies v5.78 RFWD3 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: RFWD3.
Tag Q1_25_ promote_green was removed from gene: RFWD3.
Fetal anomalies v5.78 RAP1B Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: RAP1B.
Tag Q1_25_ promote_green was removed from gene: RAP1B.
Fetal anomalies v5.78 RAB34 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: RAB34.
Tag Q1_25_ promote_green was removed from gene: RAB34.
Fetal anomalies v5.78 PUM1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: PUM1.
Tag Q1_25_ promote_green was removed from gene: PUM1.
Fetal anomalies v5.78 PSMF1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: PSMF1.
Tag Q1_25_ promote_green was removed from gene: PSMF1.
Fetal anomalies v5.78 PLS3 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: PLS3.
Tag Q1_25_ promote_green was removed from gene: PLS3.
Rhabdomyolysis and metabolic muscle disorders v5.4 ATP2A2 Sarah Leigh Classified gene: ATP2A2 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v5.4 ATP2A2 Sarah Leigh Gene: atp2a2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v5.78 PLD1 Achchuthan Shanmugasundram Tag Q1_25_ demote_amber was removed from gene: PLD1.
Tag Q1_25_ NHS_review was removed from gene: PLD1.
Tag Q2_24_expert_review was removed from gene: PLD1.
Fetal anomalies v5.78 PKDCC Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: PKDCC.
Tag Q1_25_ promote_green was removed from gene: PKDCC.
Fetal anomalies v5.78 PIP5K1C Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: PIP5K1C.
Tag Q1_25_ promote_green was removed from gene: PIP5K1C.
Fetal anomalies v5.78 PIGS Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: PIGS.
Tag Q1_25_ promote_green was removed from gene: PIGS.
Fetal anomalies v5.78 PI4K2A Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: PI4K2A.
Tag Q1_25_ promote_green was removed from gene: PI4K2A.
Fetal anomalies v5.78 PAN2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: PAN2.
Tag Q1_25_ promote_green was removed from gene: PAN2.
Rhabdomyolysis and metabolic muscle disorders v5.3 ATP2A2 Sarah Leigh gene: ATP2A2 was added
gene: ATP2A2 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Q1_25_ promote_green tags were added to gene: ATP2A2.
Mode of inheritance for gene: ATP2A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2A2 were set to 39970126
Phenotypes for gene: ATP2A2 were set to Dominant rhabdomyolysis
Review for gene: ATP2A2 was set to GREEN
Added comment: PMID: 39970126 reports a rare heterozygous missense ATP2A2 (alias symbol: SERCA2) variant (12:110777348G>A, c.1583G>A, p.R528Q) in 14 affected individuals from three unrelated families with recurrent rhabdomyolysis (an unaffected 6 year old child also carried the variant, however, symptoms of rhabdomyolysis may develop as he gets older). Haplotype analysis confirmed that the families were not related. In vitro and in vivo studies suggest that the variant affects ATP2A2 normal function, resulting in abnormal intracellular Ca2+ homeostasis in skeletal muscle, resulting in rhabdomyolysis.
Morphant zebrafish embryos (atp2a2a knockdown) had morphological and functional muscle abnormalities, including a reduced body length and trunk muscle area and a reduced locomotor activity in zebrafish larvae. This phenotype was rescued by wild-type human ATP2A2 mRNA but not variant ATP2A2 mRNA.
Sources: Literature
Fetal anomalies v5.78 NUDT2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: NUDT2.
Tag Q1_25_ promote_green was removed from gene: NUDT2.
Fetal anomalies v5.78 NSUN6 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: NSUN6.
Tag Q1_25_ promote_green was removed from gene: NSUN6.
Fetal anomalies v5.78 NLRP3 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: NLRP3.
Tag Q1_25_ promote_green was removed from gene: NLRP3.
Fetal anomalies v5.78 MYBBP1A Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: MYBBP1A.
Tag Q3_24_NHS_review was removed from gene: MYBBP1A.
Fetal anomalies v5.78 MSTO1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: MSTO1.
Tag Q1_24_MOI was removed from gene: MSTO1.
Fetal anomalies v5.78 MDFIC Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: MDFIC.
Tag Q2_24_promote_green was removed from gene: MDFIC.
Fetal anomalies v5.78 MAX Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: MAX.
Tag Q1_25_ promote_green was removed from gene: MAX.
Fetal anomalies v5.78 MAP4K4 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: MAP4K4.
Tag Q1_25_ promote_green was removed from gene: MAP4K4.
Fetal anomalies v5.78 LOX Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: LOX.
Tag Q1_25_ promote_green was removed from gene: LOX.
Fetal anomalies v5.78 LNPK Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: LNPK.
Tag Q1_25_ promote_green was removed from gene: LNPK.
Fetal anomalies v5.78 LIPT2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: LIPT2.
Tag Q1_25_ promote_green was removed from gene: LIPT2.
Fetal anomalies v5.78 LAMB2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: LAMB2.
Tag Q1_25_ promote_green was removed from gene: LAMB2.
Fetal anomalies v5.78 LAMA5 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: LAMA5.
Tag Q1_25_ promote_green was removed from gene: LAMA5.
Fetal anomalies v5.78 KMT2B Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: KMT2B.
Tag Q1_25_ promote_green was removed from gene: KMT2B.
Fetal anomalies v5.78 KIF5B Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: KIF5B.
Tag Q1_25_ promote_green was removed from gene: KIF5B.
Fetal anomalies v5.78 KIF24 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: KIF24.
Tag Q1_25_ promote_green was removed from gene: KIF24.
Fetal anomalies v5.78 KDM2B Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: KDM2B.
Tag Q1_25_ promote_green was removed from gene: KDM2B.
Fetal anomalies v5.78 KDELR2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: KDELR2.
Tag Q1_25_ promote_green was removed from gene: KDELR2.
Fetal anomalies v5.78 KCNK9 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: KCNK9.
Tag Q2_24_NHS_review was removed from gene: KCNK9.
Fetal anomalies v5.78 KCNK3 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: KCNK3.
Tag Q1_25_ promote_green was removed from gene: KCNK3.
Fetal anomalies v5.78 INTS11 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: INTS11.
Tag Q1_25_ promote_green was removed from gene: INTS11.
Fetal anomalies v5.78 HECTD4 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: HECTD4.
Tag Q1_25_ promote_green was removed from gene: HECTD4.
Fetal anomalies v5.78 GON4L Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: GON4L.
Tag Q1_25_ promote_green was removed from gene: GON4L.
Fetal anomalies v5.78 GNB2 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: GNB2.
Tag Q2_24_NHS_review was removed from gene: GNB2.
Fetal anomalies v5.78 FUZ Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: FUZ.
Tag Q1_25_ promote_green was removed from gene: FUZ.
Fetal anomalies v5.78 FTO Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: FTO.
Tag Q1_25_ promote_green was removed from gene: FTO.
Fetal anomalies v5.78 FOXP4 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: FOXP4.
Tag Q1_25_ promote_green was removed from gene: FOXP4.
Fetal anomalies v5.78 FOSL2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: FOSL2.
Tag Q1_25_ promote_green was removed from gene: FOSL2.
Fetal anomalies v5.78 FN1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: FN1.
Tag Q1_25_ promote_green was removed from gene: FN1.
Fetal anomalies v5.78 FILIP1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: FILIP1.
Tag Q1_25_ promote_green was removed from gene: FILIP1.
Fetal anomalies v5.78 FAS Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: FAS.
Tag Q1_25_ promote_green was removed from gene: FAS.
Fetal anomalies v5.78 ERI1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: ERI1.
Tag Q1_25_ promote_green was removed from gene: ERI1.
Fetal anomalies v5.78 ENG Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: ENG.
Tag Q1_25_ promote_green was removed from gene: ENG.
Fetal anomalies v5.78 EMG1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: EMG1.
Tag Q1_23_promote_green was removed from gene: EMG1.
Fetal anomalies v5.78 EFCAB1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: EFCAB1.
Tag Q1_25_ promote_green was removed from gene: EFCAB1.
Fetal anomalies v5.78 DRG1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: DRG1.
Tag Q1_25_ promote_green was removed from gene: DRG1.
Fetal anomalies v5.78 DPYSL5 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: DPYSL5.
Tag Q1_25_ promote_green was removed from gene: DPYSL5.
Fetal anomalies v5.78 DLG5 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: DLG5.
Tag Q1_25_ promote_green was removed from gene: DLG5.
Fetal anomalies v5.78 DHX30 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: DHX30.
Tag Q1_25_ promote_green was removed from gene: DHX30.
Fetal anomalies v5.78 DDRGK1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: DDRGK1.
Tag Q1_25_ promote_green was removed from gene: DDRGK1.
Fetal anomalies v5.78 CSGALNACT1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: CSGALNACT1.
Tag Q1_25_ promote_green was removed from gene: CSGALNACT1.
Fetal anomalies v5.78 CNOT2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: CNOT2.
Tag Q1_25_ promote_green was removed from gene: CNOT2.
Fetal anomalies v5.78 CEP295 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: CEP295.
Tag Q1_25_ promote_green was removed from gene: CEP295.
Fetal anomalies v5.78 CDK10 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: CDK10.
Tag Q1_25_ promote_green was removed from gene: CDK10.
Fetal anomalies v5.78 CDH2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: CDH2.
Tag Q1_25_ promote_green was removed from gene: CDH2.
Fetal anomalies v5.78 CBY1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: CBY1.
Tag Q1_25_ promote_green was removed from gene: CBY1.
Fetal anomalies v5.78 CASP2 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: CASP2.
Tag Q1_25_ promote_green was removed from gene: CASP2.
Fetal anomalies v5.78 CACNA1S Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: CACNA1S.
Tag Q1_25_ promote_green was removed from gene: CACNA1S.
Fetal anomalies v5.78 C16orf62 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: C16orf62.
Tag Q1_25_ promote_green was removed from gene: C16orf62.
Fetal anomalies v5.78 ATG7 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: ATG7.
Tag Q1_25_ promote_green was removed from gene: ATG7.
Fetal anomalies v5.78 ASXL3 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: ASXL3.
Tag Q1_25_ promote_green was removed from gene: ASXL3.
Fetal anomalies v5.78 AMOTL1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: AMOTL1.
Tag Q1_25_ promote_green was removed from gene: AMOTL1.
Fetal anomalies v5.78 AL117258.1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: AL117258.1.
Tag Q1_25_ promote_green was removed from gene: AL117258.1.
Fetal anomalies v5.78 ADD1 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: ADD1.
Tag Q1_25_ promote_green was removed from gene: ADD1.
Fetal anomalies v5.78 ADAMTS15 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: ADAMTS15.
Tag Q1_25_ promote_green was removed from gene: ADAMTS15.
Fetal anomalies v5.78 ACBD6 Achchuthan Shanmugasundram Tag Q1_25_ NHS_review was removed from gene: ACBD6.
Tag Q1_25_ promote_green was removed from gene: ACBD6.
Fetal anomalies v5.78 ZRSR2 Achchuthan Shanmugasundram edited their review of gene: ZRSR2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to X-LINKED: hemizygous mutation in males, biallelic mutations in females following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v5.78 ZFX Achchuthan Shanmugasundram edited their review of gene: ZFX: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) in females following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Fetal anomalies v5.78 WDR44 Achchuthan Shanmugasundram edited their review of gene: WDR44: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to X-LINKED: hemizygous mutation in males, biallelic mutations in females following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v5.78 WBP4 Achchuthan Shanmugasundram edited their review of gene: WBP4: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 WASHC5 Achchuthan Shanmugasundram edited their review of gene: WASHC5: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 USP14 Achchuthan Shanmugasundram commented on gene: USP14: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Fetal anomalies v5.78 UFSP2 Achchuthan Shanmugasundram edited their review of gene: UFSP2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 U2AF2 Achchuthan Shanmugasundram edited their review of gene: U2AF2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 TSHZ3 Achchuthan Shanmugasundram edited their review of gene: TSHZ3: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 TRIT1 Achchuthan Shanmugasundram edited their review of gene: TRIT1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 TONSL Achchuthan Shanmugasundram edited their review of gene: TONSL: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 TOGARAM1 Achchuthan Shanmugasundram edited their review of gene: TOGARAM1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 THSD1 Achchuthan Shanmugasundram edited their review of gene: THSD1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 TBR1 Achchuthan Shanmugasundram edited their review of gene: TBR1: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 TAF8 Achchuthan Shanmugasundram edited their review of gene: TAF8: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 SNF8 Achchuthan Shanmugasundram edited their review of gene: SNF8: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 SNAP25 Achchuthan Shanmugasundram edited their review of gene: SNAP25: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 SMPD1 Achchuthan Shanmugasundram edited their review of gene: SMPD1: Added comment: The rating of this gene has been updated to amber following NHS Genomic Medicine Service approval.; Changed rating: AMBER
Fetal anomalies v5.78 SLC4A10 Achchuthan Shanmugasundram edited their review of gene: SLC4A10: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 SLC34A1 Achchuthan Shanmugasundram edited their review of gene: SLC34A1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 SLC25A4 Achchuthan Shanmugasundram edited their review of gene: SLC25A4: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 SETD1A Achchuthan Shanmugasundram edited their review of gene: SETD1A: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v5.78 SCYL2 Achchuthan Shanmugasundram edited their review of gene: SCYL2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 SASS6 Achchuthan Shanmugasundram edited their review of gene: SASS6: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 RSPRY1 Achchuthan Shanmugasundram edited their review of gene: RSPRY1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 RSPO2 Achchuthan Shanmugasundram edited their review of gene: RSPO2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 RRAS Achchuthan Shanmugasundram edited their review of gene: RRAS: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v5.78 RRAGC Achchuthan Shanmugasundram edited their review of gene: RRAGC: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 RPL13 Achchuthan Shanmugasundram edited their review of gene: RPL13: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v5.78 ROBO1 Achchuthan Shanmugasundram edited their review of gene: ROBO1: Added comment: The mode of inheritance of this gene has been updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 RNU4-2 Achchuthan Shanmugasundram edited their review of gene: RNU4-2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 RFWD3 Achchuthan Shanmugasundram edited their review of gene: RFWD3: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 RAP1B Achchuthan Shanmugasundram edited their review of gene: RAP1B: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 RAB34 Achchuthan Shanmugasundram edited their review of gene: RAB34: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 PUM1 Achchuthan Shanmugasundram edited their review of gene: PUM1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 PSMF1 Achchuthan Shanmugasundram edited their review of gene: PSMF1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 PLS3 Achchuthan Shanmugasundram edited their review of gene: PLS3: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) in females following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Fetal anomalies v5.78 PLD1 Achchuthan Shanmugasundram edited their review of gene: PLD1: Added comment: The rating of this gene has been updated to amber following NHS Genomic Medicine Service approval.; Changed rating: AMBER
Fetal anomalies v5.78 PKDCC Achchuthan Shanmugasundram edited their review of gene: PKDCC: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 PIP5K1C Achchuthan Shanmugasundram edited their review of gene: PIP5K1C: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 PIGS Achchuthan Shanmugasundram edited their review of gene: PIGS: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 PI4K2A Achchuthan Shanmugasundram edited their review of gene: PI4K2A: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 PAN2 Achchuthan Shanmugasundram edited their review of gene: PAN2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 NUDT2 Achchuthan Shanmugasundram edited their review of gene: NUDT2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 NSUN6 Achchuthan Shanmugasundram edited their review of gene: NSUN6: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 NLRP3 Achchuthan Shanmugasundram edited their review of gene: NLRP3: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 MYBBP1A Achchuthan Shanmugasundram reviewed gene: MYBBP1A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 MSTO1 Achchuthan Shanmugasundram edited their review of gene: MSTO1: Added comment: The mode of inheritance of this gene has been updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 MDFIC Achchuthan Shanmugasundram commented on gene: MDFIC: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Fetal anomalies v5.78 MAX Achchuthan Shanmugasundram edited their review of gene: MAX: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 MAP4K4 Achchuthan Shanmugasundram edited their review of gene: MAP4K4: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 LOX Achchuthan Shanmugasundram edited their review of gene: LOX: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 LNPK Achchuthan Shanmugasundram edited their review of gene: LNPK: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 LIPT2 Achchuthan Shanmugasundram edited their review of gene: LIPT2: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 LAMB2 Achchuthan Shanmugasundram edited their review of gene: LAMB2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 LAMA5 Achchuthan Shanmugasundram edited their review of gene: LAMA5: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 KMT2B Achchuthan Shanmugasundram edited their review of gene: KMT2B: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 KIF5B Achchuthan Shanmugasundram edited their review of gene: KIF5B: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 KIF26A Achchuthan Shanmugasundram edited their review of gene: KIF26A: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 KIF24 Achchuthan Shanmugasundram edited their review of gene: KIF24: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 KDM2B Achchuthan Shanmugasundram edited their review of gene: KDM2B: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 KDELR2 Achchuthan Shanmugasundram edited their review of gene: KDELR2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 KCNK9 Achchuthan Shanmugasundram commented on gene: KCNK9: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) following NHS Genomic Medicine Service approval.
Fetal anomalies v5.78 KCNK3 Achchuthan Shanmugasundram edited their review of gene: KCNK3: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 KCNC3 Achchuthan Shanmugasundram edited their review of gene: KCNC3: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 INTS11 Achchuthan Shanmugasundram edited their review of gene: INTS11: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 HECTD4 Achchuthan Shanmugasundram edited their review of gene: HECTD4: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 GON4L Achchuthan Shanmugasundram edited their review of gene: GON4L: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 GNB2 Achchuthan Shanmugasundram commented on gene: GNB2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Fetal anomalies v5.78 FUZ Achchuthan Shanmugasundram edited their review of gene: FUZ: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 FTO Achchuthan Shanmugasundram edited their review of gene: FTO: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 FOXP4 Achchuthan Shanmugasundram edited their review of gene: FOXP4: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v5.78 FOSL2 Achchuthan Shanmugasundram edited their review of gene: FOSL2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 FN1 Achchuthan Shanmugasundram edited their review of gene: FN1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v5.78 FILIP1 Achchuthan Shanmugasundram edited their review of gene: FILIP1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 FAS Achchuthan Shanmugasundram edited their review of gene: FAS: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v5.78 ESAM Achchuthan Shanmugasundram commented on gene: ESAM: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Fetal anomalies v5.78 ERI1 Achchuthan Shanmugasundram edited their review of gene: ERI1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 ENG Achchuthan Shanmugasundram edited their review of gene: ENG: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 EMG1 Achchuthan Shanmugasundram edited their review of gene: EMG1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 EFCAB1 Achchuthan Shanmugasundram edited their review of gene: EFCAB1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 DRG1 Achchuthan Shanmugasundram edited their review of gene: DRG1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 DPYSL5 Achchuthan Shanmugasundram edited their review of gene: DPYSL5: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 DLG5 Achchuthan Shanmugasundram edited their review of gene: DLG5: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 DHX30 Achchuthan Shanmugasundram edited their review of gene: DHX30: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 DDRGK1 Achchuthan Shanmugasundram edited their review of gene: DDRGK1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 DAW1 Achchuthan Shanmugasundram edited their review of gene: DAW1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 CSGALNACT1 Achchuthan Shanmugasundram edited their review of gene: CSGALNACT1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 CNOT2 Achchuthan Shanmugasundram edited their review of gene: CNOT2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 CEP295 Achchuthan Shanmugasundram edited their review of gene: CEP295: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 CDK10 Achchuthan Shanmugasundram edited their review of gene: CDK10: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 CDH2 Achchuthan Shanmugasundram edited their review of gene: CDH2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v5.78 CBY1 Achchuthan Shanmugasundram edited their review of gene: CBY1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 CASP2 Achchuthan Shanmugasundram edited their review of gene: CASP2: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 CACNA1S Achchuthan Shanmugasundram edited their review of gene: CACNA1S: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 C16orf62 Achchuthan Shanmugasundram edited their review of gene: C16orf62: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 ATG7 Achchuthan Shanmugasundram edited their review of gene: ATG7: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 ASXL3 Achchuthan Shanmugasundram edited their review of gene: ASXL3: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 AMOTL1 Achchuthan Shanmugasundram edited their review of gene: AMOTL1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.78 AL117258.1 Achchuthan Shanmugasundram edited their review of gene: AL117258.1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 ADD1 Achchuthan Shanmugasundram edited their review of gene: ADD1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v5.78 ADAMTS15 Achchuthan Shanmugasundram edited their review of gene: ADAMTS15: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.78 ACBD6 Achchuthan Shanmugasundram edited their review of gene: ACBD6: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.77 ZRSR2 Achchuthan Shanmugasundram Source Expert Review Green was added to ZRSR2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 ZFX Achchuthan Shanmugasundram Source Expert Review Green was added to ZFX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 WDR44 Achchuthan Shanmugasundram Source Expert Review Green was added to WDR44.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 WBP4 Achchuthan Shanmugasundram Source Expert Review Green was added to WBP4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 WASHC5 Achchuthan Shanmugasundram Source Expert Review Green was added to WASHC5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 USP14 Achchuthan Shanmugasundram Source NHS GMS was added to USP14.
Source Expert Review Green was added to USP14.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 UFSP2 Achchuthan Shanmugasundram Source Expert Review Green was added to UFSP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 U2AF2 Achchuthan Shanmugasundram Source Expert Review Green was added to U2AF2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 TSHZ3 Achchuthan Shanmugasundram Source Expert Review Green was added to TSHZ3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 TRIT1 Achchuthan Shanmugasundram Source Expert Review Green was added to TRIT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 TONSL Achchuthan Shanmugasundram Source Expert Review Green was added to TONSL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 TOGARAM1 Achchuthan Shanmugasundram Source Expert Review Green was added to TOGARAM1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 THSD1 Achchuthan Shanmugasundram Source Expert Review Green was added to THSD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 TBR1 Achchuthan Shanmugasundram Source Expert Review Green was added to TBR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 TAF8 Achchuthan Shanmugasundram Source Expert Review Green was added to TAF8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 SNF8 Achchuthan Shanmugasundram Source Expert Review Green was added to SNF8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 SNAP25 Achchuthan Shanmugasundram Source Expert Review Green was added to SNAP25.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 SMPD1 Achchuthan Shanmugasundram Source Expert Review Amber was added to SMPD1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Fetal anomalies v5.77 SLC4A10 Achchuthan Shanmugasundram Source Expert Review Green was added to SLC4A10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 SLC34A1 Achchuthan Shanmugasundram Source Expert Review Green was added to SLC34A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 SLC25A4 Achchuthan Shanmugasundram Source Expert Review Green was added to SLC25A4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 SETD1A Achchuthan Shanmugasundram Source Expert Review Green was added to SETD1A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 SCYL2 Achchuthan Shanmugasundram Source Expert Review Green was added to SCYL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 SASS6 Achchuthan Shanmugasundram Source Expert Review Green was added to SASS6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 RSPRY1 Achchuthan Shanmugasundram Source Expert Review Green was added to RSPRY1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 RSPO2 Achchuthan Shanmugasundram Source Expert Review Green was added to RSPO2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 RRAS Achchuthan Shanmugasundram Source Expert Review Green was added to RRAS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 RRAGC Achchuthan Shanmugasundram Source Expert Review Green was added to RRAGC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 RPL13 Achchuthan Shanmugasundram Source Expert Review Green was added to RPL13.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 ROBO1 Achchuthan Shanmugasundram Mode of inheritance for gene ROBO1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.77 RNU4-2 Achchuthan Shanmugasundram Source Expert Review Green was added to RNU4-2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 RFWD3 Achchuthan Shanmugasundram Source Expert Review Green was added to RFWD3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 RAP1B Achchuthan Shanmugasundram Source Expert Review Green was added to RAP1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 RAB34 Achchuthan Shanmugasundram Source Expert Review Green was added to RAB34.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 PUM1 Achchuthan Shanmugasundram Source Expert Review Green was added to PUM1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 PSMF1 Achchuthan Shanmugasundram Source Expert Review Green was added to PSMF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 PLS3 Achchuthan Shanmugasundram Source Expert Review Green was added to PLS3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 PLD1 Achchuthan Shanmugasundram Source Expert Review Amber was added to PLD1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Fetal anomalies v5.77 PKDCC Achchuthan Shanmugasundram Source Expert Review Green was added to PKDCC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 PIP5K1C Achchuthan Shanmugasundram Source Expert Review Green was added to PIP5K1C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 PIGS Achchuthan Shanmugasundram Source Expert Review Green was added to PIGS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 PI4K2A Achchuthan Shanmugasundram Source Expert Review Green was added to PI4K2A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 PAN2 Achchuthan Shanmugasundram Source Expert Review Green was added to PAN2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 NUDT2 Achchuthan Shanmugasundram Source Expert Review Green was added to NUDT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 NSUN6 Achchuthan Shanmugasundram Source Expert Review Green was added to NSUN6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 NLRP3 Achchuthan Shanmugasundram Source Expert Review Green was added to NLRP3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 MYBBP1A Achchuthan Shanmugasundram Source NHS GMS was added to MYBBP1A.
Source Expert Review Green was added to MYBBP1A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 MSTO1 Achchuthan Shanmugasundram Mode of inheritance for gene MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.77 MDFIC Achchuthan Shanmugasundram Source Expert Review Green was added to MDFIC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 MAX Achchuthan Shanmugasundram Source Expert Review Green was added to MAX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 MAP4K4 Achchuthan Shanmugasundram Source Expert Review Green was added to MAP4K4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 LOX Achchuthan Shanmugasundram Source Expert Review Green was added to LOX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 LNPK Achchuthan Shanmugasundram Source Expert Review Green was added to LNPK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 LIPT2 Achchuthan Shanmugasundram Source Expert Review Green was added to LIPT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 LAMB2 Achchuthan Shanmugasundram Source Expert Review Green was added to LAMB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 LAMA5 Achchuthan Shanmugasundram Source Expert Review Green was added to LAMA5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 KMT2B Achchuthan Shanmugasundram Source Expert Review Green was added to KMT2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 KIF5B Achchuthan Shanmugasundram Source Expert Review Green was added to KIF5B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 KIF26A Achchuthan Shanmugasundram Source Expert Review Green was added to KIF26A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 KIF24 Achchuthan Shanmugasundram Source Expert Review Green was added to KIF24.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 KDM2B Achchuthan Shanmugasundram Source Expert Review Green was added to KDM2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 KDELR2 Achchuthan Shanmugasundram Source Expert Review Green was added to KDELR2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 KCNK9 Achchuthan Shanmugasundram Source Expert Review Green was added to KCNK9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 KCNK3 Achchuthan Shanmugasundram Source Expert Review Green was added to KCNK3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 KCNC3 Achchuthan Shanmugasundram Source Expert Review Green was added to KCNC3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 INTS11 Achchuthan Shanmugasundram Source Expert Review Green was added to INTS11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 HECTD4 Achchuthan Shanmugasundram Source Expert Review Green was added to HECTD4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 GON4L Achchuthan Shanmugasundram Source Expert Review Green was added to GON4L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 GNB2 Achchuthan Shanmugasundram Source Expert Review Green was added to GNB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 FUZ Achchuthan Shanmugasundram Source Expert Review Green was added to FUZ.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 FTO Achchuthan Shanmugasundram Source Expert Review Green was added to FTO.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 FOXP4 Achchuthan Shanmugasundram Source Expert Review Green was added to FOXP4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 FOSL2 Achchuthan Shanmugasundram Source Expert Review Green was added to FOSL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 FN1 Achchuthan Shanmugasundram Source Expert Review Green was added to FN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 FILIP1 Achchuthan Shanmugasundram Source Expert Review Green was added to FILIP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 FAS Achchuthan Shanmugasundram Source Expert Review Green was added to FAS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 ESAM Achchuthan Shanmugasundram Source Expert Review Green was added to ESAM.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 ERI1 Achchuthan Shanmugasundram Source Expert Review Green was added to ERI1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 ENG Achchuthan Shanmugasundram Source Expert Review Green was added to ENG.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 EMG1 Achchuthan Shanmugasundram Source Expert Review Green was added to EMG1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 EFCAB1 Achchuthan Shanmugasundram Source Expert Review Green was added to EFCAB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 DRG1 Achchuthan Shanmugasundram Source Expert Review Green was added to DRG1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 DPYSL5 Achchuthan Shanmugasundram Source Expert Review Green was added to DPYSL5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 DLG5 Achchuthan Shanmugasundram Source Expert Review Green was added to DLG5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 DHX30 Achchuthan Shanmugasundram Source Expert Review Green was added to DHX30.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 DDRGK1 Achchuthan Shanmugasundram Source Expert Review Green was added to DDRGK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 DAW1 Achchuthan Shanmugasundram Source Expert Review Green was added to DAW1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 CSGALNACT1 Achchuthan Shanmugasundram Source Expert Review Green was added to CSGALNACT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 CNOT2 Achchuthan Shanmugasundram Source Expert Review Green was added to CNOT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 CEP295 Achchuthan Shanmugasundram Source Expert Review Green was added to CEP295.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 CDK10 Achchuthan Shanmugasundram Source Expert Review Green was added to CDK10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 CDH2 Achchuthan Shanmugasundram Source Expert Review Green was added to CDH2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 CBY1 Achchuthan Shanmugasundram Source Expert Review Green was added to CBY1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 CASP2 Achchuthan Shanmugasundram Source Expert Review Green was added to CASP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 CACNA1S Achchuthan Shanmugasundram Source Expert Review Green was added to CACNA1S.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 C16orf62 Achchuthan Shanmugasundram Source Expert Review Green was added to C16orf62.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 ATG7 Achchuthan Shanmugasundram Source Expert Review Green was added to ATG7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 ASXL3 Achchuthan Shanmugasundram Source Expert Review Green was added to ASXL3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v5.77 AMOTL1 Achchuthan Shanmugasundram Source Expert Review Green was added to AMOTL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)