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Retinoblastoma v0.3 Mafalda Gomes Panel types changed to GMS Rare Disease; GMS signed-off
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.1 Achchuthan Shanmugasundram Panel version 1.0 has been signed off on 2023-09-14
Factor VII deficiency v0.3 Eleanor Williams Panel types changed to GMS Rare Disease; GMS signed-off
Pulmonary alveolar microlithiasis v1.1 Mafalda Gomes Panel version 1.0 has been signed off on 2023-09-14
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.0 Achchuthan Shanmugasundram promoted panel to version 1.0
Pulmonary alveolar microlithiasis v1.0 Mafalda Gomes promoted panel to version 1.0
Pulmonary alveolar microlithiasis v0.3 Mafalda Gomes Panel types changed to GMS Rare Disease; GMS signed-off
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.10 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease; GMS signed-off
Factor V deficiency v1.1 Eleanor Williams Panel version 1.0 has been signed off on 2023-09-14
PTEN Hamartoma Tumour Syndrome v1.1 Mafalda Gomes Panel version 1.0 has been signed off on 2023-09-14
Agammaglobulinaemia with absent BTK expression v1.1 Achchuthan Shanmugasundram Panel version 1.0 has been signed off on 2023-09-14
PTEN Hamartoma Tumour Syndrome v1.0 Mafalda Gomes promoted panel to version 1.0
PTEN Hamartoma Tumour Syndrome v0.3 Mafalda Gomes Panel types changed to GMS Rare Disease; GMS signed-off
Factor V deficiency v1.0 Eleanor Williams promoted panel to version 1.0
Factor V deficiency v0.3 Eleanor Williams Panel types changed to GMS Rare Disease; GMS signed-off
Agammaglobulinaemia with absent BTK expression v1.0 Achchuthan Shanmugasundram promoted panel to version 1.0
Agammaglobulinaemia with absent BTK expression v0.9 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease; GMS signed-off
Pseudoxanthoma elasticum v1.1 Mafalda Gomes Panel version 1.0 has been signed off on 2023-09-14
Pseudoxanthoma elasticum v1.0 Mafalda Gomes promoted panel to version 1.0
Pseudoxanthoma elasticum v0.3 Mafalda Gomes Panel types changed to GMS Rare Disease; GMS signed-off
Factor IX deficiency v1.1 Eleanor Williams Panel version 1.0 has been signed off on 2023-09-14
Acute intermittent porphyria v1.1 Achchuthan Shanmugasundram Panel version 1.0 has been signed off on 2023-09-14
Factor IX deficiency v1.0 Eleanor Williams promoted panel to version 1.0
Primary hyperaldosteronism - KCNJ5 v1.1 Mafalda Gomes Panel version 1.0 has been signed off on 2023-09-14
Acute intermittent porphyria v1.0 Achchuthan Shanmugasundram promoted panel to version 1.0
Factor IX deficiency v0.3 Eleanor Williams Panel types changed to GMS Rare Disease; GMS signed-off
Primary hyperaldosteronism - KCNJ5 v1.0 Mafalda Gomes promoted panel to version 1.0
Primary hyperaldosteronism - KCNJ5 v0.3 Mafalda Gomes Panel types changed to GMS Rare Disease; GMS signed-off
Acute intermittent porphyria v0.10 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease; GMS signed-off
Early onset or syndromic epilepsy v4.101 RAB5C Achchuthan Shanmugasundram Classified gene: RAB5C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.101 RAB5C Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence (4 unrelated cases) for this gene to be promoted to green rating in this panel at the next GMS update.
Early onset or syndromic epilepsy v4.101 RAB5C Achchuthan Shanmugasundram Gene: rab5c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.100 RAB5C Achchuthan Shanmugasundram Deleted their review
Early onset or syndromic epilepsy v4.100 RAB5C Achchuthan Shanmugasundram Entity copied from Intellectual disability - microarray and sequencing v5.285
Early onset or syndromic epilepsy v4.100 RAB5C Achchuthan Shanmugasundram gene: RAB5C was added
gene: RAB5C was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q3_23_promote_green tags were added to gene: RAB5C.
Mode of inheritance for gene: RAB5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB5C were set to 37552066
Phenotypes for gene: RAB5C were set to Neurodevelopmental disorder MONDO:0700092, RAB5C-related
Intellectual disability v5.285 RAB5C Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence for this gene to be promoted to green rating at the next GMS update.; to: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence (12 unrelated cases) for this gene to be promoted to green rating at the next GMS update.
Intellectual disability v5.285 RAB5C Achchuthan Shanmugasundram Classified gene: RAB5C as Amber List (moderate evidence)
Intellectual disability v5.285 RAB5C Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence for this gene to be promoted to green rating at the next GMS update.
Intellectual disability v5.285 RAB5C Achchuthan Shanmugasundram Gene: rab5c has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.284 RAB5C Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: RAB5C.
White matter disorders and cerebral calcification - narrow panel v3.17 ESAM Achchuthan Shanmugasundram Tag Q3_23_NHS_review was removed from gene: ESAM.
Early onset or syndromic epilepsy v4.99 ESAM Achchuthan Shanmugasundram Tag Q3_23_NHS_review was removed from gene: ESAM.
White matter disorders and cerebral calcification - narrow panel v3.17 ESAM Achchuthan Shanmugasundram Entity copied from Intellectual disability - microarray and sequencing v5.284
White matter disorders and cerebral calcification - narrow panel v3.17 ESAM Achchuthan Shanmugasundram gene: ESAM was added
gene: ESAM was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert Review Amber,Literature,Expert Review
Q3_23_promote_green, Q3_23_NHS_review tags were added to gene: ESAM.
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity, OMIM:620371
Early onset or syndromic epilepsy v4.99 ESAM Achchuthan Shanmugasundram Entity copied from Intellectual disability - microarray and sequencing v5.284
Early onset or syndromic epilepsy v4.99 ESAM Achchuthan Shanmugasundram gene: ESAM was added
gene: ESAM was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature,Expert Review
Q3_23_promote_green, Q3_23_NHS_review tags were added to gene: ESAM.
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity, OMIM:620371
Intellectual disability v5.284 ESAM Achchuthan Shanmugasundram changed review comment from: As reviewed by Julia Baptista, PMID:36996813 reported the identification of biallelic ESAM variants in 13 individuals from eight unrelated families, which included four foetuses. All nine born individuals had profound global developmental delay/ unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/ cerebral calcifications, the latter being also observed in the foetuses.

This gene has been associated with relevant phenotypes in OMIM (MIM #620371), but not yet in Gene2Phenotype.; to: As reviewed by Julia Baptista, PMID:36996813 reported the identification of biallelic ESAM variants in 13 individuals from eight unrelated families, which included four foetuses. All nine live-born individuals had profound global developmental delay/ unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/ cerebral calcifications, the latter being also observed in the foetuses.

This gene has been associated with relevant phenotypes in OMIM (MIM #620371), but not yet in Gene2Phenotype.
Intellectual disability v5.284 ESAM Achchuthan Shanmugasundram Classified gene: ESAM as Amber List (moderate evidence)
Intellectual disability v5.284 ESAM Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating in the next GMS review.
Intellectual disability v5.284 ESAM Achchuthan Shanmugasundram Gene: esam has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.283 ESAM Achchuthan Shanmugasundram Phenotypes for gene: ESAM were changed from severe ID; seizures, spasticity to Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity, OMIM:620371
Intellectual disability v5.282 ESAM Achchuthan Shanmugasundram Publications for gene: ESAM were set to PMID: 36996813
Intellectual disability v5.281 ESAM Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: ESAM.
Tag Q3_23_NHS_review tag was added to gene: ESAM.
Intellectual disability v5.281 ESAM Achchuthan Shanmugasundram reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 36996813; Phenotypes: Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity, OMIM:620371; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.98 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.97 PPP1R3F Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.; to: Comment on list classification: There are at least six patients reported with epilepsy and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Early onset or syndromic epilepsy v4.97 PPP1R3F Achchuthan Shanmugasundram changed review comment from: PMID:37531237 - 13 unrelated males were identified with hemizygous variants in PPP1R3F gene and were reported with a novel X-linked recessive neurodevelopmental disorder. Intellectual disability was formally tested in 10 individuals of which 5 had mild ID, two had severe ID, one had moderate ID, one had ID for which severity was not stated and one had no ID.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:37531237 - 13 unrelated males were identified with hemizygous variants in PPP1R3F gene and were reported with a novel X-linked recessive neurodevelopmental disorder. Six of these 13 patients were reported with heterogeneous seizure types including generalized, nocturnal, tonic, atonic, focal, myoclonic, and atypical absence.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Early onset or syndromic epilepsy v4.97 PPP1R3F Achchuthan Shanmugasundram edited their review of gene: PPP1R3F: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.97 PPP1R3F Achchuthan Shanmugasundram Entity copied from Intellectual disability - microarray and sequencing v5.281
Early onset or syndromic epilepsy v4.97 PPP1R3F Achchuthan Shanmugasundram gene: PPP1R3F was added
gene: PPP1R3F was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
Q3_23_promote_green tags were added to gene: PPP1R3F.
Mode of inheritance for gene: PPP1R3F was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PPP1R3F were set to 37531237
Phenotypes for gene: PPP1R3F were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Classified gene: PPP1R3F as Amber List (moderate evidence)
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Gene: ppp1r3f has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Classified gene: PPP1R3F as Amber List (moderate evidence)
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Gene: ppp1r3f has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Classified gene: PPP1R3F as Amber List (moderate evidence)
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Gene: ppp1r3f has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Classified gene: PPP1R3F as Amber List (moderate evidence)
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Gene: ppp1r3f has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Classified gene: PPP1R3F as Amber List (moderate evidence)
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Gene: ppp1r3f has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Classified gene: PPP1R3F as Amber List (moderate evidence)
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.281 PPP1R3F Achchuthan Shanmugasundram Gene: ppp1r3f has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.280 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.279 PPP1R3F Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PPP1R3F.
Intellectual disability v5.279 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.280 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.280 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.280 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.279 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.278 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.279 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.278 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related
Intellectual disability v5.278 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related
Intellectual disability v5.278 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related
Intellectual disability v5.277 PPP1R3F Achchuthan Shanmugasundram reviewed gene: PPP1R3F: Rating: GREEN; Mode of pathogenicity: None; Publications: 37531237; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v5.277 NR2F2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: NR2F2.
Tag Q3_23_NHS_review tag was added to gene: NR2F2.
Intellectual disability v5.277 NR2F2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.277 NR2F2 Achchuthan Shanmugasundram Classified gene: NR2F2 as Amber List (moderate evidence)
Intellectual disability v5.277 NR2F2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating in the next GMS review.
Intellectual disability v5.277 NR2F2 Achchuthan Shanmugasundram Gene: nr2f2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.277 NR2F2 Achchuthan Shanmugasundram Classified gene: NR2F2 as Amber List (moderate evidence)
Intellectual disability v5.277 NR2F2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating in the next GMS review.
Intellectual disability v5.277 NR2F2 Achchuthan Shanmugasundram Gene: nr2f2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.276 NR2F2 Achchuthan Shanmugasundram changed review comment from: This gene is an established gene for congenital heart defects (MIM #615779) and disorder of sexual differentiation (MIM #618901). This gene has been associated with these two phenotypes in both OMIM and Gene2Phenotype.

PMID:29663647 - An 11-month old boy was reported with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect and was identified with pathogenic NR2F2 variant.

PMID:37500725 - 16 previously unreported unrelated individuals (and a mildly affected mosaic mother of one of them) with rare heterozygous variants (majority are de novo variants) were reviewed in this publication and they had variable clinical presentations including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations. All 14 for whom data is available had motor delays and 13 had speech delay. One of them had global developmental delay, one had mild intellectual disability and four had learning disabilities.; to: This gene is an established gene for congenital heart defects (MIM #615779) and disorder of sexual differentiation (MIM #618901). This gene has been associated with these two phenotypes in both OMIM and Gene2Phenotype. Some patients with CHD (MIM #615779) are reported with developmental delays in the OMIM record.

PMID:29663647 - An 11-month old boy was reported with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect and was identified with pathogenic NR2F2 variant.

PMID:37500725 - 16 previously unreported unrelated individuals (and a mildly affected mosaic mother of one of them) with rare heterozygous variants (majority are de novo variants) were reviewed in this publication and they had variable clinical presentations including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations. All 14 for whom data is available had motor delays and 13 had speech delay. One of them had global developmental delay, one had mild intellectual disability and four had learning disabilities.
Intellectual disability v5.276 NR2F2 Achchuthan Shanmugasundram changed review comment from: This gene is an established gene for congenital heart defects (MIM #615779) and disorder of sexual differentiation (MIM #618901).

PMID:29663647 - An 11-month old boy was reported with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect and was identified with pathogenic NR2F2 variant.

PMID:37500725 - 16 previously unreported unrelated individuals (and a mildly affected mosaic mother of one of them) with rare heterozygous variants (majority are de novo variants) were reviewed in this publication and they had variable clinical presentations including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations. All 14 for whom data is available had motor delays and 13 had speech delay. One of them had global developmental delay, one had mild intellectual disability and four had learning disabilities.; to: This gene is an established gene for congenital heart defects (MIM #615779) and disorder of sexual differentiation (MIM #618901). This gene has been associated with these two phenotypes in both OMIM and Gene2Phenotype.

PMID:29663647 - An 11-month old boy was reported with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect and was identified with pathogenic NR2F2 variant.

PMID:37500725 - 16 previously unreported unrelated individuals (and a mildly affected mosaic mother of one of them) with rare heterozygous variants (majority are de novo variants) were reviewed in this publication and they had variable clinical presentations including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations. All 14 for whom data is available had motor delays and 13 had speech delay. One of them had global developmental delay, one had mild intellectual disability and four had learning disabilities.
Intellectual disability v5.276 NR2F2 Achchuthan Shanmugasundram Publications for gene: NR2F2 were set to 29663647; 37500725
Intellectual disability v5.276 NR2F2 Achchuthan Shanmugasundram Publications for gene: NR2F2 were set to 29663647; 37500725
Intellectual disability v5.276 NR2F2 Achchuthan Shanmugasundram Publications for gene: NR2F2 were set to
Intellectual disability v5.275 NR2F2 Achchuthan Shanmugasundram Mode of inheritance for gene: NR2F2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.275 NR2F2 Achchuthan Shanmugasundram Mode of inheritance for gene: NR2F2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.275 NR2F2 Achchuthan Shanmugasundram Mode of inheritance for gene: NR2F2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.275 NR2F2 Achchuthan Shanmugasundram Mode of inheritance for gene: NR2F2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.274 NR2F2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.274 NR2F2 Achchuthan Shanmugasundram commented on gene: NR2F2: This gene is an established gene for congenital heart defects (MIM #615779) and disorder of sexual differentiation (MIM #618901).

PMID:29663647 - An 11-month old boy was reported with global developmental delay, dysmorphic features, coarctation of the aorta, and ventricular septal defect and was identified with pathogenic NR2F2 variant.

PMID:37500725 - 16 previously unreported unrelated individuals (and a mildly affected mosaic mother of one of them) with rare heterozygous variants (majority are de novo variants) were reviewed in this publication and they had variable clinical presentations including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations. All 14 for whom data is available had motor delays and 13 had speech delay. One of them had global developmental delay, one had mild intellectual disability and four had learning disabilities.
Intellectual disability v5.274 NR2F2 Achchuthan Shanmugasundram reviewed gene: NR2F2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29663647, 37500725; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.96 U2AF2 Achchuthan Shanmugasundram Tag Q3_23_NHS_review was removed from gene: U2AF2.
Early onset or syndromic epilepsy v4.96 U2AF2 Achchuthan Shanmugasundram edited their review of gene: U2AF2: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.96 U2AF2 Achchuthan Shanmugasundram Entity copied from Intellectual disability - microarray and sequencing v5.274
Early onset or syndromic epilepsy v4.96 U2AF2 Achchuthan Shanmugasundram gene: U2AF2 was added
gene: U2AF2 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
Q3_23_promote_green, Q3_23_NHS_review tags were added to gene: U2AF2.
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Phenotypes for gene: U2AF2 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: U2AF2.
Tag Q3_23_NHS_review tag was added to gene: U2AF2.
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.275 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Phenotypes for gene: U2AF2 were changed from Developmental disorders to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.274 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.273 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.273 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Intellectual disability v5.273 U2AF2 Achchuthan Shanmugasundram Publications for gene: U2AF2 were set to 33057194
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram edited their review of gene: U2AF2: Changed publications to: 28135719, 31785789, 33057194, 34112922, 36747105, 37092751, 37134193
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Classified gene: U2AF2 as Amber List (moderate evidence)
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Celia Duff, there is sufficient evidence (>3 unrelated cases) available for the association of this gene with global developmental delay, intellectual disability and epilepsy. Hence, this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Classified gene: U2AF2 as Amber List (moderate evidence)
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Celia Duff, there is sufficient evidence (>3 unrelated cases) available for the association of this gene with global developmental delay, intellectual disability and epilepsy. Hence, this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Classified gene: U2AF2 as Amber List (moderate evidence)
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Celia Duff, there is sufficient evidence (>3 unrelated cases) available for the association of this gene with global developmental delay, intellectual disability and epilepsy. Hence, this gene should be promoted to green rating at the next GMS review.
Intellectual disability v5.272 U2AF2 Achchuthan Shanmugasundram Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.271 U2AF2 Achchuthan Shanmugasundram reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 31785789, 34112922, 36747105, 37092751, 37134193; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
NARP syndrome or maternally inherited Leigh syndrome v0.2 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Adult onset dystonia, chorea or related movement disorder v3.13 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Retinal disorders v4.24 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Mitochondrial disorders v4.93 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Likely inborn error of metabolism v4.49 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Undiagnosed metabolic disorders v1.600 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Adult onset neurodegenerative disorder v4.35 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Optic neuropathy v4.11 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Structural basal ganglia disorders v1.38 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Albinism or congenital nystagmus v3.1 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Early onset dystonia v1.135 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Infantile nystagmus v1.10 MT-ND6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND6.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-ND5 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND5.
Mitochondrial disorders v4.93 MT-ND5 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND5.
Likely inborn error of metabolism v4.49 MT-ND5 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND5.
Undiagnosed metabolic disorders v1.600 MT-ND5 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND5.
Hereditary ataxia with onset in adulthood v4.22 RFC1 Sarah Leigh Deleted their comment
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-ND4L Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4L.
Mitochondrial disorders v4.93 MT-ND4L Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4L.
Likely inborn error of metabolism v4.49 MT-ND4L Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4L.
Undiagnosed metabolic disorders v1.600 MT-ND4L Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4L.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4.
Retinal disorders v4.24 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4.
Mitochondrial disorders v4.93 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4.
Intellectual disability v5.271 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4.
Likely inborn error of metabolism v4.49 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4.
Undiagnosed metabolic disorders v1.600 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4.
Optic neuropathy v4.11 MT-ND4 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND4.
Undiagnosed metabolic disorders v1.600 MT-ND3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND3.
Mitochondrial disorders v4.93 MT-ND3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND3.
Likely inborn error of metabolism v4.49 MT-ND3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND3.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-ND3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND3.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND2.
Mitochondrial disorders v4.93 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND2.
Likely inborn error of metabolism v4.49 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND2.
Undiagnosed metabolic disorders v1.600 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND2.
Albinism or congenital nystagmus v3.1 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND2.
Infantile nystagmus v1.10 MT-ND2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND2.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND1.
Adult onset dystonia, chorea or related movement disorder v3.13 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND1.
Retinal disorders v4.24 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND1.
Mitochondrial disorders v4.93 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND1.
Intellectual disability v5.271 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND1.
Likely inborn error of metabolism v4.49 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND1.
Undiagnosed metabolic disorders v1.600 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND1.
Optic neuropathy v4.11 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND1.
Structural basal ganglia disorders v1.38 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND1.
Sudden death in young people v1.15 MT-ND1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ND1.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CYB.
Mitochondrial disorders v4.93 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CYB.
Likely inborn error of metabolism v4.49 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CYB.
Undiagnosed metabolic disorders v1.600 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CYB.
Albinism or congenital nystagmus v3.1 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CYB.
Sudden death in young people v1.15 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CYB.
Infantile nystagmus v1.10 MT-CYB Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CYB.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO3.
Mitochondrial disorders v4.93 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO3.
Early onset or syndromic epilepsy v4.95 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO3.
Likely inborn error of metabolism v4.49 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO3.
Undiagnosed metabolic disorders v1.600 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO3.
Albinism or congenital nystagmus v3.1 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO3.
Infantile nystagmus v1.10 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO3.
Acute rhabdomyolysis v1.15 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO2.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO2.
Mitochondrial disorders v4.93 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO2.
Likely inborn error of metabolism v4.49 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO2.
Undiagnosed metabolic disorders v1.600 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO2.
Rhabdomyolysis and metabolic muscle disorders v3.35 MT-CO2 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO2.
Structural eye disease v3.4 ARHGAP35 Hannah Knight gene: ARHGAP35 was added
gene: ARHGAP35 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to 36450800
Phenotypes for gene: ARHGAP35 were set to Anophthalmia; microphthalmia; coloboma
Review for gene: ARHGAP35 was set to GREEN
Added comment: Novel damaging variants in ARHGAP35 were identified in five individuals with developmental ocular disorders from four families
Family 1 - father and daughter with microphthalmia. c.4251delC p.(Thr1418Argfs*381) shared by both affected individuals. This variant was not present in five unaffected family members: mother, brother, paternal grandmother, and two paternal aunts
Family 2 - simplex case of a boy with corneal opacity with cataract, iris hypoplasia, and glaucoma treated with keratoprostheses. De novo variant identified c.4444delC p.(Gln1482Serfs*317)
Family 3 - simplex case of a boy with bilateral microphthalmia. De novo variant identified c.1849C > T p.(Arg617Ter)
Family 4 - adult male patient with bilateral anophthalmia. Trio exome sequencing identified a novel variant in ARHGAP35, c.4294 T > C p.(Cys1432Arg), inherited from the father, who did not have a MAC phenotype but was reported to wear glasses from a young age with no further details available. Labelled as a VUS
Sources: Literature
Acute rhabdomyolysis v1.15 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO1.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO1.
Mitochondrial disorders v4.93 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO1.
Likely inborn error of metabolism v4.49 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO1.
Undiagnosed metabolic disorders v1.600 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO1.
Albinism or congenital nystagmus v3.1 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO1.
Rhabdomyolysis and metabolic muscle disorders v3.35 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO1.
Infantile nystagmus v1.10 MT-CO1 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO1.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP8.
Mitochondrial disorders v4.93 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP8.
Likely inborn error of metabolism v4.49 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP8.
Undiagnosed metabolic disorders v1.600 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP8.
Skeletal muscle channelopathy v3.1 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP8.
Paroxysmal central nervous system disorders v3.8 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP8.
Skeletal Muscle Channelopathies v1.45 MT-ATP8 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP8.
Structural eye disease v3.4 PDGFRA Hannah Knight gene: PDGFRA was added
gene: PDGFRA was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: PDGFRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDGFRA were set to 35034853
Phenotypes for gene: PDGFRA were set to Bilateral chorioretinal coloboma, microphthalmia and global developmental delay
Review for gene: PDGFRA was set to AMBER
Added comment: PMID: 35034853 - patient with bilateral chorioretinal coloboma and microphthalmia as well as global developmental delay with autistic behavior. Heterozygous variant in PDGFRA found - NM_006206.6:c.1295C>T, p.(Thr432Met). Not found in unaffected mother
Knockdown of pdgfaa and pdgfab in zebrafish caused a severe coloboma phenotype
Sources: Literature
Structural eye disease v3.4 CDH4 Hannah Knight gene: CDH4 was added
gene: CDH4 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: CDH4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDH4 were set to 35034853
Phenotypes for gene: CDH4 were set to Iris coloboma, intellectual disability, and microcephaly
Review for gene: CDH4 was set to AMBER
Added comment: PMID: 35034853 - patient with an iris coloboma, intellectual disability, and microcephaly. Heterozygous variant in CDH4 found - NM_001794.5:c.1291C>T, p.(Arg431Cys). Not found in unaffected mother
Knockdown of cdh4 in zebrafish led to ocular maldevelopment (as has been previously reported)
Sources: Literature
Hereditary neuropathy or pain disorder v3.56 VWA1 Sarah Leigh Tag STR tag was added to gene: VWA1.
Structural eye disease v3.4 BMPR1B Hannah Knight gene: BMPR1B was added
gene: BMPR1B was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: BMPR1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMPR1B were set to 35034853
Phenotypes for gene: BMPR1B were set to Ocular coloboma
Review for gene: BMPR1B was set to GREEN
Added comment: Four unrelated families with BMPR1B variants reported:
1. Two affected siblings with bilateral optic disc coloboma. Mother confirmed heterozygote - NM_001203.2:c.272G>T, p.(Arg91Ile)
2. Single proband with unilateral right microphthalmia, right dense cataract and persistent hyperplastic primary vitreous. No family history. De novo variant - NM_001203.2:c.1127G>A, p.(Arg376Glu)
3. Patient with bilateral iris and chorioretinal coloboma - c.671G>A, p.(Arg224His)
4. Patient with right iris and bilateral chorioretinal coloboma - c.671G>T, p.(Arg224Leu)
Sources: Literature
Structural eye disease v3.4 ALX1 Hannah Knight reviewed gene: ALX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32914578; Phenotypes: Frontonasal Dysplasia 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v3.4 ANK3 Hannah Knight gene: ANK3 was added
gene: ANK3 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: ANK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK3 were set to 35034853
Phenotypes for gene: ANK3 were set to Ocular coloboma
Review for gene: ANK3 was set to AMBER
Added comment: PMID: 35034853 identified two patients with ocular coloboma, each with a different heterozygous missense mutation in ANK3. In one of these families, the variant was confirmed as de novo. In the other, the unaffected mother was confirmed not to carry it.
Knockdown of ank3a and ank3b in zebrafish resulted in microphthalmia and penetrant coloboma phenotype
Sources: Literature
NARP syndrome or maternally inherited Leigh syndrome v0.2 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Childhood onset dystonia, chorea or related movement disorder v3.48 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Hereditary neuropathy or pain disorder v3.56 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Adult onset dystonia, chorea or related movement disorder v3.13 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Retinal disorders v4.24 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Hereditary ataxia with onset in adulthood v4.22 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Mitochondrial disorders v4.93 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Intellectual disability v5.271 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Hereditary neuropathy v1.472 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Likely inborn error of metabolism v4.49 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Undiagnosed metabolic disorders v1.600 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Adult onset neurodegenerative disorder v4.35 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Skeletal muscle channelopathy v3.1 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Optic neuropathy v4.11 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Paroxysmal central nervous system disorders v3.8 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Structural basal ganglia disorders v1.38 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Albinism or congenital nystagmus v3.1 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Hereditary ataxia v1.331 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Ataxia and cerebellar anomalies - narrow panel v4.34 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Skeletal Muscle Channelopathies v1.45 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Infantile nystagmus v1.10 MT-ATP6 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-ATP6.
Wiskott-Aldrich syndrome v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Wilson disease v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
von Willebrand disease v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Von Hippel Lindau syndrome v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Variegate porphyria v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Tuberous sclerosis v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Thiamine metabolism dysfunction syndrome 2 v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Thanatophoric dysplasia v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Sickle cell, thalassaemia and other haemoglobinopathies v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Tay-Sachs disease v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Syndromic and non syndromic craniosynostosis involving midline sutures v0.3 Achchuthan Shanmugasundram Panel status changed from internal to public
Subcutaneous panniculitis T-cell lymphoma (SPTCL) v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Spinal muscular atrophy type 1 rare mutation testing v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Smith-Lemli-Opitz syndrome v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Sitosterolaemia v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Short stature - SHOX deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Severe combined immunodeficiency with PNP deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Severe combined immunodeficiency with adenosine deaminase deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Segmental or atypical neurofibromatosis type 1 testing v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
SCID with features of gamma chain deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Sandhoff disease v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Retinoblastoma v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Pulmonary alveolar microlithiasis v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
PTEN Hamartoma Tumour Syndrome v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Pseudoxanthoma elasticum v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Primary hyperaldosteronism - KCNJ5 v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
POLG-related disorder v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Phenylketonuria v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Peutz Jeghers Syndrome v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Nijmegen breakage syndrome v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Niemann-Pick disease type A or B v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Niemann Pick disease type C v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Neutropaenia consistent with ELANE mutations v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Neuronal ceroid lipofuscinosis type 2 v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Neurofibromatosis type 1 (GMS) v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Neonatal diabetes - small panel v0.3 Achchuthan Shanmugasundram Panel status changed from internal to public
NARP syndrome or maternally inherited Leigh syndrome v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Multiple exostoses v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Multiple endocrine neoplasia type 2 v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Mucopolysaccharidosis type VI v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Mucopolysaccharidosis type IVA v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Mucopolysaccharidosis type IIIB v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Mucopolysaccharidosis type IIIA v0.3 Achchuthan Shanmugasundram Panel status changed from internal to public
Mucopolysaccharidosis type II v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Mucopolysaccharidosis type IH or S v0.4 Achchuthan Shanmugasundram Panel status changed from internal to public
Mucolipidosis II and III Alpha or Beta v0.4 Achchuthan Shanmugasundram Panel status changed from internal to public
Monitoring for G(M)CSF escape mutations v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Mitochondrial neurogastrointestinal encephalopathy v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Mitochondrial Complex V deficiency, TMEM70 type v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Lysosomal acid lipase deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Lymphoproliferative syndrome with absent SAP expression v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Krabbe disease - Saposin A deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Krabbe disease - GALC deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Inherited parathyroid cancer v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Incontinentia pigmenti v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Hereditary angioedema types I and II v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Haemophagocytic syndrome with absent XIAP expression v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Haemophagocytic syndrome with absent perforin expression v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Glycogen storage disease V v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Glucokinase-related fasting hyperglycaemia v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Generalised arterial calcification in infancy v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Gaucher disease v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Fumarate hydratase-related tumour syndromes v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Familial tumours of the nervous system v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Familial dysalbuminaemic hyperthyroxinaemia v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Factor XIII deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Factor XI deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Factor X deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Factor VIII deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Factor VII deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Factor V deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Factor IX deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Factor II deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Facioscapulohumeral muscular dystrophy - extended testing v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Fabry disease v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Elastin-related phenotypes v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Duchenne or Becker muscular dystrophy v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
DICER1-related cancer predisposition v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Cystinosis v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Cystic fibrosis diagnostic test v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Congenital adrenal hyperplasia diagnostic test v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Combined vitamin K-dependent clotting factor deficiency v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Central congenital hypoventilation v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Carney complex v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Calcium-sensing receptor phenotypes v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
CADASIL v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Blepharophimosis ptosis and epicanthus inversus v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Beckwith-Wiedemann syndrome v0.3 Achchuthan Shanmugasundram Panel status changed from internal to public
Barth syndrome v0.2 Achchuthan Shanmugasundram Panel status changed from internal to public
BAP1 associated tumour predisposition syndrome v0.3 Achchuthan Shanmugasundram Panel status changed from internal to public
Autoimmune Polyendocrine Syndrome v0.3 Achchuthan Shanmugasundram Panel status changed from internal to public
Autoimmune lymphoproliferative syndrome with defective apoptosis v0.7 Achchuthan Shanmugasundram Panel status changed from internal to public
Ataxia telangiectasia - mutation testing v0.8 Achchuthan Shanmugasundram Panel status changed from internal to public
APC associated Polyposis v0.9 Achchuthan Shanmugasundram Panel status changed from internal to public
Alveolar capillary dysplasia with misalignment of pulmonary veins v0.7 Achchuthan Shanmugasundram Panel status changed from internal to public
Alstrom syndrome v0.7 Achchuthan Shanmugasundram Panel status changed from internal to public
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.9 Achchuthan Shanmugasundram Panel status changed from internal to public
Agammaglobulinaemia with absent BTK expression v0.8 Achchuthan Shanmugasundram Panel status changed from internal to public
Acute intermittent porphyria v0.9 Achchuthan Shanmugasundram Panel status changed from internal to public
Early onset or syndromic epilepsy v4.95 STARD7 Sarah Leigh Tag STR tag was added to gene: STARD7.
Hereditary ataxia with onset in adulthood v4.22 FGF14_GAA Sarah Leigh Phenotypes for STR: FGF14_GAA were changed from Late-onset cerebellar ataxia; Episodic features; Nystagmus; Spinocerebellar ataxia 27B, late-onset, OMIM:620174 to Spinocerebellar ataxia 27B, late-onset, OMIM: 620174
Hereditary ataxia with onset in adulthood v4.21 FGF14_GAA Sarah Leigh Publications for STR: FGF14_GAA were set to 36516086; 36493768
Corneal dystrophy v3.5 TCF4 Sarah Leigh Deleted their comment
Corneal dystrophy v3.5 TCF4 Sarah Leigh Publications for gene: TCF4 were set to 29526280; 26401622; 24255041; 25168903; 25722209; 25593321
Early onset or syndromic epilepsy v4.95 SAMD12 Sarah Leigh Publications for gene: SAMD12 were set to 30194086; 29507423; 29939203; 32203200
Intellectual disability v5.271 PPP1R3F Zornitza Stark gene: PPP1R3F was added
gene: PPP1R3F was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: PPP1R3F was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PPP1R3F were set to 37531237
Phenotypes for gene: PPP1R3F were set to Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related
Review for gene: PPP1R3F was set to GREEN
Added comment: 13 unrelated hemizygous individuals reported with functional evidence
Sources: Literature
Intellectual disability v5.271 RAB5C Zornitza Stark gene: RAB5C was added
gene: RAB5C was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: RAB5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB5C were set to 37552066
Phenotypes for gene: RAB5C were set to Neurodevelopmental disorder MONDO:0700092, RAB5C-related
Review for gene: RAB5C was set to GREEN
Added comment: 12 individuals with nine different heterozygous de novo variants in RAB5C.
9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe).
All have mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD).
Sources: Literature
Skeletal dysplasia v4.18 AXIN1 Zornitza Stark gene: AXIN1 was added
gene: AXIN1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: AXIN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AXIN1 were set to 37582359
Phenotypes for gene: AXIN1 were set to Syndromic disease, (MONDO:0002254), AXIN1-related; skeletal dysplasia
Review for gene: AXIN1 was set to GREEN
Added comment: PMID: 37582359
- four families (7 individuals) with three homozygous truncating variants.
- all variant shown to result in reduced protein, though 1/3 would be NMD predicted
- Probands had macrocephaly (4/6), GDD (3/7), hip dysplasia (5/6), cardiac anomalies eg. VSD/ASD (3/7), cranial hyperostosis and vertebral endplate sclerosis
Sources: Literature
Ichthyosis and erythrokeratoderma v3.3 DBR1 Zornitza Stark gene: DBR1 was added
gene: DBR1 was added to Ichthyosis and erythrokeratoderma. Sources: Literature
Mode of inheritance for gene: DBR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DBR1 were set to 37656279
Phenotypes for gene: DBR1 were set to Ichthyosis (MONDO#0019269), DBR1-related
Review for gene: DBR1 was set to AMBER
Added comment: PMID: 37656279:
- A homozygous missense as a founder recessive DBR1 variant in four consanguineous families.
- Total of 7 affected children. WES done for one proband from each family.
- Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life.
- RNA and protein studies using fibroblasts derived from a patient are supportive of pathogenicity: RNA-seq, rt-qPCR and western blotting, showing marked reduction of DBR1 level and intronic RNA lariat accumulation in the patient sample.
- Haplotype analysis revealed that the four families all share a haplotype extending at least 2.27 Mb around the c.200A>G p.(Tyr67Cys) DBR1 founder variant.
- Authors proposed this is a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility, and highlighted the apparent lack of correlation with the degree of DBR1 deficiency.
Sources: Literature
Paediatric or syndromic cardiomyopathy v3.30 CAP2 Zornitza Stark gene: CAP2 was added
gene: CAP2 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: CAP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAP2 were set to 30518548; 33083013; 34862840
Phenotypes for gene: CAP2 were set to Cardiomyopathy, dilated, 2I (MIM#620462)
Review for gene: CAP2 was set to GREEN
Added comment: Four individuals from three families with homozygous variants and early onset DCM. Knockout mouse model shows DCM and cardiac conduction disease.

PMID: 33083013: Cheema
Homozygous nonsense (p.(Tyr316*)) reported in a DCM and heart failure patient. Two siblings deceased due to DCM but not tested.

PMID: 34862840: Gurunathan
Homozygous PTC identified in an infant with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction. Carrier parents unaffected.

PMID: 30518548: Aspit
Homozygous canonical splice variant in two cousins from a consanguineous family with DCM. All carriers unaffected. Knockout mouse model shows DCM and cardiac conduction disease.
Sources: Literature
Gaucher disease v0.1 GBA Eleanor Williams commented on gene: GBA
Barth syndrome v0.1 TAZ Eleanor Williams commented on gene: TAZ
NARP syndrome or maternally inherited Leigh syndrome v0.1 MT-ATP6 Eleanor Williams commented on gene: MT-ATP6
NARP syndrome or maternally inherited Leigh syndrome v0.1 MT-ATP6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ATP6.
NARP syndrome or maternally inherited Leigh syndrome v0.1 MT-ND6 Eleanor Williams commented on gene: MT-ND6
NARP syndrome or maternally inherited Leigh syndrome v0.1 MT-ND6 Eleanor Williams Tag gene-checked tag was added to gene: MT-ND6.
Familial tumours of the nervous system v0.1 DGCR8 Eleanor Williams commented on gene: DGCR8
Familial tumours of the nervous system v0.1 DGCR8 Eleanor Williams Tag gene-checked tag was added to gene: DGCR8.
Primary lymphoedema v3.3 ERG Andrew Mumford gene: ERG was added
gene: ERG was added to Primary lymphoedema. Sources: Research
Mode of inheritance for gene: ERG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ERG were set to primary lymphoedema
Penetrance for gene: ERG were set to Complete
Review for gene: ERG was set to GREEN
Added comment: The association between monoallelic high impact LoF variants in ERG was identified in 4 independent pedigrees in the 100KGP RD main programme and supported by functional evidence of ERG functionality in lymphatic endothelial cells (PMID:36928819)
Sources: Research
Monogenic hearing loss v4.14 GPR156 Andrew Mumford gene: GPR156 was added
gene: GPR156 was added to Monogenic hearing loss. Sources: Research
Mode of inheritance for gene: GPR156 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPR156 were set to PMID:36928829
Phenotypes for gene: GPR156 were set to sensorineural hearing loss
Penetrance for gene: GPR156 were set to Complete
Review for gene: GPR156 was set to GREEN
Added comment: The association between biallelic LoF variants in GPR156 and non-syndromic sensorineural hearing loss was identified in an association analysis in the 100KGP RD main programme in two pedigrees and replicated in a further large independent pedigree (reported in PMID:36928819). A causal association is supported by replication of the phenotype in a GPR156-/- mouse model and credible mechanistic evidence in primary cel cultures (PMID:34001891).
Sources: Research
Thoracic aortic aneurysm or dissection (GMS) v3.1 PMEPA1 Andrew Mumford gene: PMEPA1 was added
gene: PMEPA1 was added to Thoracic aortic aneurysm or dissection (GMS). Sources: Research
Mode of inheritance for gene: PMEPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMEPA1 were set to PMID:36928819
Phenotypes for gene: PMEPA1 were set to thoracic aortic aneurysm; tall stature; dolichocephaly; abnormal axial skeletal morphology; pes planus
Penetrance for gene: PMEPA1 were set to Complete
Review for gene: PMEPA1 was set to GREEN
Added comment: Association between chain truncation variants in cytoplasmic domain of PMEPA1 and 'Loeys-Dietz' phenotype was established in an association analysis in 100KGP RD main programme, but reproduced in multiple independent pedigrees reported in PMID:36928819. Gene encodes regulator of TGFBeta signalling, a pathway implicated in other familial thoracic aneurysm disorders.
Sources: Research
Intellectual disability v5.271 NR2F2 Katherine Lachlan reviewed gene: NR2F2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37500725; Phenotypes: intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, vascular malformations; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.271 ATM Zornitza Stark reviewed gene: ATM: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Ataxia-telangiectasia, MIM#208900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v3.30 LDB3 Dmitrijs Rots reviewed gene: LDB3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36253531; Phenotypes: dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cystic kidney disease v4.6 PRKCSH Ian Berry changed review comment from: Phenotype is predominantly hepatic but can involve renal cysts.

We have seen 2x patients with pathogenic findings in this gene through R193 referrals therefore it makes sense to be on this panel. R193 referrals frequently have both renal & hepatic cysts.; to: Phenotype is predominantly hepatic but can involve renal cysts.

We have seen 2x patients with pathogenic findings in this gene through R193 referrals therefore it makes sense to be on this panel. R193 referrals frequently have both renal & hepatic cysts.

OMIM disorder name is polycystic liver disease-1 with or without kidney cysts (PCLD1)
Cystic kidney disease v4.6 SEC63 Ian Berry changed review comment from: Phenotype is predominantly hepatic but can involve renal cysts.

We have seen 2x patients with pathogenic findings in this gene through R193 referrals therefore it makes sense to be on this panel. R193 referrals frequently have both renal & hepatic cysts.; to: Phenotype is predominantly hepatic but can involve renal cysts.

We have seen 2x patients with pathogenic findings in this gene through R193 referrals therefore it makes sense to be on this panel. R193 referrals frequently have both renal & hepatic cysts.

OMIM disorder name is polycystic liver disease-2 with or without kidney cysts (PCLD2)
Cystic kidney disease v4.6 SEC63 Ian Berry reviewed gene: SEC63: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cystic kidney disease v4.6 PRKCSH Ian Berry reviewed gene: PRKCSH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.271 ESAM Julia Baptista gene: ESAM was added
gene: ESAM was added to Intellectual disability - microarray and sequencing. Sources: Literature,Expert Review
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to PMID: 36996813
Phenotypes for gene: ESAM were set to severe ID; seizures, spasticity
Review for gene: ESAM was set to GREEN
Added comment: Lecca et al 2023 reported thirteen patients from eight unrelated families with biallelic loss of function variants (nonsense, frameshift, canonical splice site, all predicted to result in a transcript targeted for nonsense-mediated decay). Protein staining assays in one of the brain fetal samples confirmed loss the loss of protein.
The phenotype reported in this cohort is of a severe neurodevelopmental disorder with brain anomalies (calcifications, hydrocephalus, enlarged ventricles, cerebral atrophy, etc), and dysmorphic features.
Sources: Literature, Expert Review
Fetal anomalies v3.109 ESAM Julia Baptista gene: ESAM was added
gene: ESAM was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to PMID: 36996813
Phenotypes for gene: ESAM were set to intracranial hemorrhage; cerebral anomalies
Review for gene: ESAM was set to GREEN
Added comment: Four fetuses from three unrelated families (different LOF biallelic variants) with fetal intracranial hemorrhage. Fetal brain tissue from one of the affected individuals at 31 weeks' gestational age showed lack of ESAM staining in the capillary endothelial cells, thus confirming loss of ESAM. Another individual had an abnormal prenatal ultrasound and the pregnancy was terminated at 32 weeks' gestation, but no DNA was available to test for the familial variant.
Neurodevelopmental disorder with cerebral calcifications, hydrocephalus, focal white matter lesions, retina anomalies and dysmorphic features.
Sources: Literature
Severe early-onset obesity v4.7 ADCY3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants of this gene to obesity.

The phenotypes of biallelic variants appear severe and early-onset. The age of patients with monoallelic variants ranged from 28 and 57 and its was not clear whether the patients had either monogenic or common form of obesity. Hence, the MOIU should be set as "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal".; to: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants of this gene to obesity and this gene can be promoted to green rating at the next major update.

The phenotypes of biallelic variants appear severe and early-onset. The age of patients with monoallelic variants ranged from 28 and 57 and its was not clear whether the patients had either monogenic or common form of obesity. Hence, the MOI should be set as "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal".
Rhabdomyolysis and metabolic muscle disorders v3.35 AMPD1 Zornitza Stark reviewed gene: AMPD1: Rating: RED; Mode of pathogenicity: None; Publications: 21343608, 27296017; Phenotypes: Myopathy due to myoadenylate deaminase deficiency (MIM#615511); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe early-onset obesity v4.7 ADCY3 Achchuthan Shanmugasundram Classified gene: ADCY3 as Amber List (moderate evidence)
Severe early-onset obesity v4.7 ADCY3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants of this gene to obesity.

The phenotypes of biallelic variants appear severe and early-onset. The age of patients with monoallelic variants ranged from 28 and 57 and its was not clear whether the patients had either monogenic or common form of obesity. Hence, the MOIU should be set as "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal".
Severe early-onset obesity v4.7 ADCY3 Achchuthan Shanmugasundram Gene: adcy3 has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v4.6 ADCY3 Achchuthan Shanmugasundram Phenotypes for gene: ADCY3 were changed from Monogenic severe obesity to Monogenic severe obesity; {Obesity, susceptibility to, BMIQ19}, OMIM:617885
Severe early-onset obesity v4.5 ADCY3 Achchuthan Shanmugasundram changed review comment from: PMID:29311636 - Founder canonical splice variant (c.2433-1G>A) reported in Greenlandic populations demonstrate higher risk of obesity and type 2 diabetes in homozygous individuals.

PMID:29311637 - Four children from three consanguineous Pakistani families were reported with severe early-onset obesity and identified with three different homozygous variants in ADCY3 gene. In addition, an obese boy of European-American descent was identified with heterozygous ADCY3 variants.

PMID:35026759 - Two additional heterozygous variants (c.1658C>T/ p.Ala553Val & c.489C>G/ p.His163Gln) were identified in six Qatari individuals with obesity. However, the authors of this publication struggle to draw a conclusion on the impact of the dominant effect of the variants due to the genetic and biological overlap between monogenic and the common form of obesity.; to: PMID:29311636 - Founder canonical splice variant (c.2433-1G>A) reported in Greenlandic populations demonstrate higher risk of obesity and type 2 diabetes in homozygous individuals.

PMID:29311637 - Four children from three consanguineous Pakistani families were reported with severe early-onset obesity and identified with three different homozygous variants in ADCY3 gene. In addition, an obese boy of European-American descent was identified with heterozygous ADCY3 variants.

PMID:35026759 - Two additional heterozygous variants (c.1658C>T/ p.Ala553Val & c.489C>G/ p.His163Gln) were identified in six Qatari individuals with obesity. However, the authors of this publication struggle to draw a conclusion on the impact of the dominant effect of the variants due to the genetic and biological overlap between monogenic and the common form of obesity.

Autosomal recessive variants in this gene have been associated with phenotype in OMIM (MIM #617885). But, dominant variants have not yet been associated with relevant phenotypes in OMIM.
Severe early-onset obesity v4.5 ADCY3 Achchuthan Shanmugasundram edited their review of gene: ADCY3: Changed publications to: 29311636, 29311637, 35026759
Severe early-onset obesity v4.5 ADCY3 Achchuthan Shanmugasundram Publications for gene: ADCY3 were set to 2931163; 29311637; 35026759
Severe early-onset obesity v4.4 ADCY3 Achchuthan Shanmugasundram Publications for gene: ADCY3 were set to 29311637; 35026759
Severe early-onset obesity v4.3 ADCY3 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: ADCY3.
Severe early-onset obesity v4.3 ADCY3 Achchuthan Shanmugasundram edited their review of gene: ADCY3: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Severe early-onset obesity v4.3 ADCY3 Achchuthan Shanmugasundram reviewed gene: ADCY3: Rating: GREEN; Mode of pathogenicity: None; Publications: 2931163, 29311637, 35026759; Phenotypes: {Obesity, susceptibility to, BMIQ19}, OMIM:617885; Mode of inheritance: None
Intellectual disability v5.271 TP63 Arina Puzriakova Phenotypes for gene: TP63 were changed from Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome; 3, 604292; Split-hand/foot malformation 4, 605289; Hay-Wells syndrome, 106260; ADULT syndrome, 103285; Limb-mammary syndrome, 603543; Rapp-Hodgkin syndrome, 129400; Orofacial cleft 8, 129400 to ADULT syndrome, OMIM:103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Hay-Wells syndrome, OMIM:106260; Limb-mammary syndrome, OMIM:603543; Orofacial cleft 8, OMIM:618149; Rapp-Hodgkin syndrome, OMIM:129400; Split-hand/foot malformation 4, OMIM:605289
Clefting v4.95 TP63 Arina Puzriakova Phenotypes for gene: TP63 were changed from Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3, 604292; Orofacial cleft 8, EEC SYNDROME 3, Rapp Hodgkins syndrome, 129400; EEC syndrome (Ectrodactyly, Ectodermal dysplasia and Clefting); AEC (Ankyloblepharon filiforme adnatum, Ectodermal defects and Clefting), Hay Wells syndrome 106260; Limb-mammary syndrome, 603543; ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3; EEC3; Cleft lip to Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Hay-Wells syndrome, OMIM:106260; Limb-mammary syndrome, OMIM:603543; Orofacial cleft 8, OMIM:618149; Rapp-Hodgkin syndrome, OMIM:129400; Split-hand/foot malformation 4, OMIM:605289
Fetal anomalies v3.109 TP63 Arina Puzriakova Phenotypes for gene: TP63 were changed from ECTODERMAL DYSPLASIA RAPP-HODGKIN TYPE; ECTRODACTYLY-ECTODERMAL DYSPLASIA-CLEFT LIP/PALATE SYNDROME TYPE 3; SPLIT-HAND/FOOT MALFORMATION TYPE 4; ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE; LIMB-MAMMARY SYNDROME; NON-SYNDROMIC OROFACIAL CLEFT TYPE 8; ACRO-DERMATO-UNGUAL-LACRIMAL-TOOTH SYNDROME to ADULT syndrome, OMIM:103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Hay-Wells syndrome, OMIM:106260; Limb-mammary syndrome, OMIM:603543; Orofacial cleft 8, OMIM:618149; Rapp-Hodgkin syndrome, OMIM:129400; Split-hand/foot malformation 4, OMIM:605289
Ectodermal dysplasia without a known gene mutation v1.24 TP63 Arina Puzriakova Phenotypes for gene: TP63 were changed from Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, 604292; Split-hand/foot malformation 4, 605289; Hay-Wells syndrome, 106260; ADULT syndrome, 103285; Limb-mammary syndrome, 603543; Rapp-Hodgkin syndrome, 129400; Orofacial cleft 8, 129400; Orofac; Adult Syndrome; Ankyloblepharon-Ectodermal Defects-Cleft Lip/palate; Ectrodactyly, Ectodermal Dysplasia, And Cleft Lip/palate Syndrome 3; Limb-Mammary Syndrome; Rapp-Hodgkin Syndrome; Split-Hand/foot Malformation 4; ECTODERMAL DYSPLASIA RAPP-HODGKIN TYPE; ECTRODACTYLY-ECTODERMAL DYSPLASIA-CLEFT LIP/PALATE SYNDROME TYPE 3; ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE to ADULT syndrome, OMIM:103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Hay-Wells syndrome, OMIM:106260; Limb-mammary syndrome, OMIM:603543; Rapp-Hodgkin syndrome, OMIM:129400; Split-hand/foot malformation 4, OMIM:605289
Ectodermal dysplasia v3.8 TP63 Arina Puzriakova Phenotypes for gene: TP63 were changed from Limb-mammary syndrome, 603543; Rapp-Hodgkin Syndrome; ADULT syndrome, 103285; Orofac; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, 604292; Ankyloblepharon-Ectodermal Defects-Cleft Lip/palate; Orofacial cleft 8, 129400; Hay-Wells syndrome, 106260; ECTRODACTYLY-ECTODERMAL DYSPLASIA-CLEFT LIP/PALATE SYNDROME TYPE 3; Split-Hand/foot Malformation 4; Split-hand/foot malformation 4, 605289; ECTODERMAL DYSPLASIA RAPP-HODGKIN TYPE; Rapp-Hodgkin syndrome, 129400; Limb-Mammary Syndrome; ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE; Ectrodactyly, Ectodermal Dysplasia, And Cleft Lip/palate Syndrome 3; Adult Syndrome to ADULT syndrome, OMIM:103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Hay-Wells syndrome, OMIM:106260; Limb-mammary syndrome, OMIM:603543; Rapp-Hodgkin syndrome, OMIM:129400; Split-hand/foot malformation 4, OMIM:605289
Skeletal dysplasia v4.18 TP63 Arina Puzriakova Phenotypes for gene: TP63 were changed from ADULT syndrome, OMIM:103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Limb-mammary syndrome, OMIM:603543 to ADULT syndrome, OMIM:103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Limb-mammary syndrome, OMIM:603543; Split-hand/foot malformation 4, OMIM:605289
Limb disorders v4.9 TP63 Arina Puzriakova Phenotypes for gene: TP63 were changed from ADULT syndrome, OMIM:103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Limb-mammary syndrome, OMIM:603543 to ADULT syndrome, OMIM:103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Limb-mammary syndrome, OMIM:603543; Split-hand/foot malformation 4, OMIM:605289
Skeletal dysplasia v4.17 TP63 Arina Puzriakova Phenotypes for gene: TP63 were changed from Rapp-Hodgkin syndrome 129400; Orofacial cleft 8 129400; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 604292; Hay-Wells syndrome 106260; ULT syndrome 103285; Split-hand/foot malformation 4 605289; Limb-mammary syndrome 603543 to ADULT syndrome, OMIM:103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Limb-mammary syndrome, OMIM:603543
Limb disorders v4.8 TP63 Arina Puzriakova Phenotypes for gene: TP63 were changed from ULT syndrome 103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 604292; Hay-Wells syndrome 106260; Limb-mammary syndrome 603543; Orofacial cleft 8 129400; Rapp-Hodgkin syndrome 129400; Split-hand/foot malformation 4 605289 to ADULT syndrome, OMIM:103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Limb-mammary syndrome, OMIM:603543
Mosaic skin disorders - deep sequencing v2.31 TP63 Arina Puzriakova Tag watchlist tag was added to gene: TP63.
Tag somatic tag was added to gene: TP63.
Mosaic skin disorders - deep sequencing v2.31 TP63 Arina Puzriakova Classified gene: TP63 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.31 TP63 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Tom Cullup (GOSH). This gene is associated with a number of phenotypes, some of which lead to dermatologic abnormalities. Mosaicism is not common - there is only one paper confirming somatic mosaicism in one individual (PMID: 18792980), plus another case mentioned by Tom Cullup from Kinsler lab. There is also a report of suspected mosaicism (but not confirmed) in a patient due to the Blaschko distributions of hypopigmented patches on their skin and hair loss (PMID: 34703865).

The phenotype fits the scope and this is likely the only panel to pick up somatic cases. However, the evidence supporting somatic mosaicism is borderline. Only one case has been published since 2008, and at least one additional confirmed case is needed to corroborate the association. Leaving rating as Amber with watchlist tag to monitor for additional evidence.
Mosaic skin disorders - deep sequencing v2.31 TP63 Arina Puzriakova Gene: tp63 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Classified gene: ERMARD as Red List (low evidence)
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Arina Puzriakova, this gene has been demoted from amber to red.
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Gene: ermard has been classified as Red List (Low Evidence).
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Classified gene: ERMARD as Red List (low evidence)
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Arina Puzriakova, this gene has been demoted from amber to red.
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Gene: ermard has been classified as Red List (Low Evidence).
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Classified gene: ERMARD as Red List (low evidence)
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Arina Puzriakova, this gene has been demoted from amber to red.
Intellectual disability v5.270 ERMARD Achchuthan Shanmugasundram Gene: ermard has been classified as Red List (Low Evidence).
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Classified gene: ERMARD as Red List (low evidence)
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Arina Puzriakova, this gene has been demoted to red.
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Gene: ermard has been classified as Red List (Low Evidence).
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Classified gene: ERMARD as Red List (low evidence)
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Arina Puzriakova, this gene has been demoted to red.
Intellectual disability v5.269 ERMARD Achchuthan Shanmugasundram Gene: ermard has been classified as Red List (Low Evidence).
Acute rhabdomyolysis v1.15 MYH1 Achchuthan Shanmugasundram Classified gene: MYH1 as Amber List (moderate evidence)
Acute rhabdomyolysis v1.15 MYH1 Achchuthan Shanmugasundram Gene: myh1 has been classified as Amber List (Moderate Evidence).
Acute rhabdomyolysis v1.14 MYH1 Achchuthan Shanmugasundram gene: MYH1 was added
gene: MYH1 was added to Acute rhabdomyolysis. Sources: Literature
Mode of inheritance for gene: MYH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYH1 were set to 33755318
Phenotypes for gene: MYH1 were set to rhabdomyolysis, MONDO:0005290
Review for gene: MYH1 was set to AMBER
Added comment: There is one patient identified with homozygous MYH1 variant (c.1295A>C; p.Lys432Thr) and a horse model with the same phenotype. Hence, this gene can be rated amber for now.
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v3.35 MYH1 Achchuthan Shanmugasundram Classified gene: MYH1 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.35 MYH1 Achchuthan Shanmugasundram Gene: myh1 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.34 MYH1 Achchuthan Shanmugasundram Mode of pathogenicity for gene: MYH1 was changed from None to None
Rhabdomyolysis and metabolic muscle disorders v3.33 MYH1 Achchuthan Shanmugasundram Mode of pathogenicity for gene: MYH1 was changed from None to None
Rhabdomyolysis and metabolic muscle disorders v3.33 MYH1 Achchuthan Shanmugasundram Mode of pathogenicity for gene: MYH1 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
Rhabdomyolysis and metabolic muscle disorders v3.32 MYH1 Achchuthan Shanmugasundram Mode of inheritance for gene: MYH1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v3.31 MYH1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Dmitrijs Rots, there is one patient identified with homozygous MYH1 variant and a horse model with the same phenotype. Hence, this gene can be rated amber for now.; to: There is one patient identified with homozygous MYH1 variant (c.1295A>C; p.Lys432Thr) and a horse model with the same phenotype. Hence, this gene can be rated amber for now.
Rhabdomyolysis and metabolic muscle disorders v3.31 MYH1 Achchuthan Shanmugasundram Publications for gene: MYH1 were set to PMID: 33755318
Rhabdomyolysis and metabolic muscle disorders v3.30 MYH1 Achchuthan Shanmugasundram Phenotypes for gene: MYH1 were changed from rhabdomyolysis, MONDO:0005290 to rhabdomyolysis, MONDO:0005290
Rhabdomyolysis and metabolic muscle disorders v3.29 MYH1 Achchuthan Shanmugasundram Phenotypes for gene: MYH1 were changed from Rhabdomyolysis to rhabdomyolysis, MONDO:0005290
Rhabdomyolysis and metabolic muscle disorders v3.28 MYH1 Achchuthan Shanmugasundram reviewed gene: MYH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33755318; Phenotypes: rhabdomyolysis, MONDO:0005290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.35 DIAPH1 Achchuthan Shanmugasundram Classified gene: DIAPH1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.35 DIAPH1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating at the next major update.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.35 DIAPH1 Achchuthan Shanmugasundram Gene: diaph1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.34 DIAPH1 Achchuthan Shanmugasundram Phenotypes for gene: DIAPH1 were changed from microcephaly; epilepsy; cortical blindness; poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. to Seizures, cortical blindness, microcephaly syndrome, OMIM:616632
Primary immunodeficiency or monogenic inflammatory bowel disease v4.33 DIAPH1 Achchuthan Shanmugasundram Publications for gene: DIAPH1 were set to PMID: 35748970; PMID: 33662367
Primary immunodeficiency or monogenic inflammatory bowel disease v4.32 DIAPH1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: DIAPH1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.32 DIAPH1 Achchuthan Shanmugasundram reviewed gene: DIAPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33662367; Phenotypes: Seizures, cortical blindness, microcephaly syndrome, OMIM:616632; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.32 OTULIN Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Boaz Palterer, there is sufficient evidence for the association of monoallelic OTULIN variants to immunodeficiency. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.32 OTULIN Achchuthan Shanmugasundram Mode of inheritance for gene: OTULIN was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.31 OTULIN Achchuthan Shanmugasundram Phenotypes for gene: OTULIN were changed from Autoinflammation, panniculitis, and dermatosis syndrome, OMIM:617099; Fever, diarrhoea, dermatitis; Autoinflammatory Disorders to {Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection}, OMIM:619986; Autoinflammation, panniculitis, and dermatosis syndrome, OMIM:617099
Primary immunodeficiency or monogenic inflammatory bowel disease v4.30 OTULIN Achchuthan Shanmugasundram Publications for gene: OTULIN were set to 27559085; 27523608
Primary immunodeficiency or monogenic inflammatory bowel disease v4.29 OTULIN Achchuthan Shanmugasundram Tag Q3_23_MOI tag was added to gene: OTULIN.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.29 OTULIN Achchuthan Shanmugasundram reviewed gene: OTULIN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: {Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection}, OMIM:619986, Autoinflammation, panniculitis, and dermatosis syndrome, OMIM:617099; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.29 DOCK11 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: DOCK11.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.29 DOCK11 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.29 DOCK11 Achchuthan Shanmugasundram Classified gene: DOCK11 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.29 DOCK11 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.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.29 DOCK11 Achchuthan Shanmugasundram Gene: dock11 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.28 DOCK11 Achchuthan Shanmugasundram Phenotypes for gene: DOCK11 were changed from early-onset autoimmunity; cytopenia; systemic lupus erythematosus; dermatitis; enteropathy to Autoinflammatory disease, multisystem, with immune dysregulation, X-linked, OMIM:301109
Primary immunodeficiency or monogenic inflammatory bowel disease v4.27 DOCK11 Achchuthan Shanmugasundram Publications for gene: DOCK11 were set to 36952639
Primary immunodeficiency or monogenic inflammatory bowel disease v4.26 DOCK11 Achchuthan Shanmugasundram reviewed gene: DOCK11: Rating: GREEN; Mode of pathogenicity: None; Publications: 36952639, 37342957; Phenotypes: Autoinflammatory disease, multisystem, with immune dysregulation, X-linked, OMIM:301109; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency or monogenic inflammatory bowel disease v4.26 ARPC5 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: ARPC5.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.26 ARPC5 Achchuthan Shanmugasundram Classified gene: ARPC5 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.26 ARPC5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least three unrelated cases and supporting functional evidence available for the association of this gene with immunodeficiency. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.26 ARPC5 Achchuthan Shanmugasundram Gene: arpc5 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.25 ARPC5 Achchuthan Shanmugasundram Phenotypes for gene: ARPC5 were changed from immunodeficiency; autoimmunity; inflammation; dysmorphisms; impaired wound healing; scoliosis; pneumatoceles; anemia to combined immunodeficiency, MONDO:0015131
Primary immunodeficiency or monogenic inflammatory bowel disease v4.24 ARPC5 Achchuthan Shanmugasundram Publications for gene: ARPC5 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v4.23 ARPC5 Achchuthan Shanmugasundram edited their review of gene: ARPC5: Changed phenotypes to: combined immunodeficiency, MONDO:0015131
Primary immunodeficiency or monogenic inflammatory bowel disease v4.23 ARPC5 Achchuthan Shanmugasundram reviewed gene: ARPC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 37349293, 37382373; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.34 DAB1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Zornitza Stark, there is only one case reported with cerebellar ataxia and identified with biallelic DAB1 variants. Hence, this gene should remain red in this panel.; to: As reviewed by Zornitza Stark, there is only one case reported with cerebellar ataxia and identified with biallelic DAB1 variants. Hence, this gene should remain red in this panel.

Note that repeat expansions in this gene have an established association with disease (MIM #615945) and it is caused by monoallelic inheritance.
Ataxia and cerebellar anomalies - narrow panel v4.34 DAB1 Achchuthan Shanmugasundram Phenotypes for gene: DAB1 were changed from Spinocerebellar ataxia 37 to cerebellar ataxia, MONDO:0000437
Ataxia and cerebellar anomalies - narrow panel v4.33 DAB1 Achchuthan Shanmugasundram Mode of inheritance for gene: DAB1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.32 DAB1 Achchuthan Shanmugasundram reviewed gene: DAB1: Rating: RED; Mode of pathogenicity: None; Publications: 33928188; Phenotypes: cerebellar ataxia, MONDO:0000437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.32 TRIP4 Achchuthan Shanmugasundram Classified gene: TRIP4 as Red List (low evidence)
Ataxia and cerebellar anomalies - narrow panel v4.32 TRIP4 Achchuthan Shanmugasundram Gene: trip4 has been classified as Red List (Low Evidence).
Ataxia and cerebellar anomalies - narrow panel v4.31 TRIP4 Achchuthan Shanmugasundram reviewed gene: TRIP4: Rating: RED; Mode of pathogenicity: None; Publications: 34075209; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.268 U2AF2 Celia Duff-Farrier changed review comment from: Literature evidence Ref1-5, identification of affected patients in the diagnostic setting (CVA database, 19:55661148:C>T ) and further accounts in open access databases (ClinVar and LOVD), make this gene suitable for clinical review and upgrading to a green gene status on relevant panels. It is associated with a phenotype encompassing dysmorphism, epilepsy, developmental delay, intellectual disability, and brain malformation Ref1-5. There is a recent publication that proposes an extension of this phenotype to include hypomyelination leukodystrophy Ref6. A loss of function mechanism has been suggested, associated with disruption of RNA recognition motifs required for the function of U2AF2 as a pre-mRNA splicing factor Ref4. At least one recurrent pathogenic variant has been identified by this review U2AF2 c.445C>T p.(Arg149Trp). U2AF2 is constrained for missense in gnomAD Z=4.71.
total variants reported
1) De novo U2AF2 (NM_007279.3:c.445C>T p.(Arg149Trp)) recurrent variant; 1x patient in Hiraide (PubMed: 34112922), 1x patient in Kittock (PubMed: 37092751), 2x patients in Kaplanis (Pubmed: 33057194), 7x patients in the Leiden Open Variation Database (LOVD, https://www.lovd.nl/), 1x patient in house BGL and 4x additional on CVA
2) De novo U2AF2 c.603G>T; 1 patient in Wang 2023 (PubMed: 36747105)
3) De novo U2AF2 c.470C>T p.Pro157Leu) in Kuroda (PubMed: 37134193)
4) 9x additional pathogenic or likely pathogenic variants on LOVD
5) 2x additional likely pathogenic variants on ClinVar

References
1.       PubMed: 28135719 McRae (2017)-DDD data
2.       PubMed: 31785789 Turner (2019)-DDD data
3.       PubMed: 34112922 Hiraide (2021) de novo U2AF2 c.445C>T p.R149W
4.       PubMed: 36747105 Wang (2023) de novo U2AF2 c.603G>T, p.163_201del
5.       PubMed: 37092751 Kittock (2023) de novo U2AF2 c.445C>T p.R149W
Possible emerging phenotype of hypomyelinating leukodystrophy
6.       PubMed: 37134193 Kuroda (2023); to: Literature evidence Ref1-5, identification of affected patients in the diagnostic setting (CVA database, 19:55661148:C>T ) and further accounts in open access databases (ClinVar and LOVD), make this gene suitable for clinical review and upgrading to a green gene status on relevant panels. It is associated with a phenotype encompassing dysmorphism, epilepsy, developmental delay, intellectual disability, and brain malformation Ref1-5. There is a recent publication that proposes an extension of this phenotype to include hypomyelination leukodystrophy Ref6. A loss of function mechanism has been suggested, associated with disruption of RNA recognition motifs required for the function of U2AF2 as a pre-mRNA splicing factor Ref4. At least one recurrent pathogenic variant has been identified by this review U2AF2 c.445C>T p.(Arg149Trp). U2AF2 is constrained for missense in gnomAD Z=4.71.
total variants/patients identified
1) De novo U2AF2 (NM_007279.3:c.445C>T p.(Arg149Trp)) recurrent variant; 1x patient in Hiraide (PubMed: 34112922), 1x patient in Kittock (PubMed: 37092751), 2x patients in Kaplanis (Pubmed: 33057194), 7x patients in the Leiden Open Variation Database (LOVD, https://www.lovd.nl/), 1x patient in house BGL and 4x additional on CVA
2) De novo U2AF2 c.603G>T; 1 patient in Wang 2023 (PubMed: 36747105)
3) De novo U2AF2 c.470C>T p.Pro157Leu) in Kuroda (PubMed: 37134193)
4) 9x additional pathogenic or likely pathogenic variants on LOVD
5) 2x additional likely pathogenic variants on ClinVar
6) We are collaborating with a researcher in the USA with a cohort of 40+ cases.


References
1.       PubMed: 28135719 McRae (2017)-DDD data
2.       PubMed: 31785789 Turner (2019)-DDD data
3.       PubMed: 34112922 Hiraide (2021) de novo U2AF2 c.445C>T p.R149W
4.       PubMed: 36747105 Wang (2023) de novo U2AF2 c.603G>T, p.163_201del
5.       PubMed: 37092751 Kittock (2023) de novo U2AF2 c.445C>T p.R149W
Possible emerging phenotype of hypomyelinating leukodystrophy
6.       PubMed: 37134193 Kuroda (2023)
Ataxia and cerebellar anomalies - narrow panel v4.31 RFXANK Achchuthan Shanmugasundram Classified gene: RFXANK as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.31 RFXANK Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, this gene should be rated amber with the current evidence.
Ataxia and cerebellar anomalies - narrow panel v4.31 RFXANK Achchuthan Shanmugasundram Gene: rfxank has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v4.30 RFXANK Achchuthan Shanmugasundram reviewed gene: RFXANK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Bare lymphocyte syndrome, type II, complementation group B, OMIM:209920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.268 U2AF2 Celia Duff-Farrier reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 28135719):(PMID: 31785789):(PMID: 34112922):(PMID: 36747105):(PMID: 37092751):(PMID 37134193); Phenotypes: intellectual disability, global developmental delay, dysmorphism, epilepsy, brain malformation, microcephaly, possible emerging phenotype of hypomyelinating leukodystrophy.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Severe microcephaly v4.31 ATP6V0C Achchuthan Shanmugasundram Tag watchlist was removed from gene: ATP6V0C.
Tag Q3_23_promote_green tag was added to gene: ATP6V0C.
Tag Q3_23_NHS_review tag was added to gene: ATP6V0C.
Severe microcephaly v4.31 ATP6V0C Achchuthan Shanmugasundram Classified gene: ATP6V0C as Amber List (moderate evidence)
Severe microcephaly v4.31 ATP6V0C Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for promoting this gene to green rating in the next GMS review.
Severe microcephaly v4.31 ATP6V0C Achchuthan Shanmugasundram Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.30 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy; Intellectual Disability; microcephaly to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Severe microcephaly v4.29 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 33190975; 33090716
Severe microcephaly v4.28 ATP6V0C Achchuthan Shanmugasundram reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 36074901; Phenotypes: Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Classified gene: NEUROG1 as Amber List (moderate evidence)
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases reported with global developmental delay/ intellectual disability. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Gene: neurog1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Classified gene: NEUROG1 as Amber List (moderate evidence)
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases reported with global developmental delay/ intellectual disability. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Gene: neurog1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Classified gene: NEUROG1 as Amber List (moderate evidence)
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases reported with global developmental delay/ intellectual disability. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability v5.268 NEUROG1 Achchuthan Shanmugasundram Gene: neurog1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.267 NEUROG1 Achchuthan Shanmugasundram Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078
Intellectual disability v5.267 NEUROG1 Achchuthan Shanmugasundram Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078
Intellectual disability v5.267 NEUROG1 Achchuthan Shanmugasundram Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078
Intellectual disability v5.267 NEUROG1 Achchuthan Shanmugasundram Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078
Intellectual disability v5.266 NEUROG1 Achchuthan Shanmugasundram Phenotypes for gene: NEUROG1 were changed from Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469 to Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469
Intellectual disability v5.267 NEUROG1 Achchuthan Shanmugasundram Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078
Intellectual disability v5.267 NEUROG1 Achchuthan Shanmugasundram Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078
Intellectual disability v5.267 NEUROG1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: NEUROG1.
Tag Q3_23_NHS_review tag was added to gene: NEUROG1.
Intellectual disability v5.267 NEUROG1 Achchuthan Shanmugasundram Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078
Intellectual disability v5.267 NEUROG1 Achchuthan Shanmugasundram Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078
Intellectual disability v5.267 NEUROG1 Achchuthan Shanmugasundram Publications for gene: NEUROG1 were set to 36647078; 33439489; 23419067; 26077850
Intellectual disability v5.266 NEUROG1 Achchuthan Shanmugasundram Phenotypes for gene: NEUROG1 were changed from Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469 to Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469
Intellectual disability v5.266 NEUROG1 Achchuthan Shanmugasundram Phenotypes for gene: NEUROG1 were changed from Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469 to Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469
Intellectual disability v5.266 NEUROG1 Achchuthan Shanmugasundram Phenotypes for gene: NEUROG1 were changed from Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469 to Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469
Intellectual disability v5.266 NEUROG1 Achchuthan Shanmugasundram Phenotypes for gene: NEUROG1 were changed from Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469 to Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469
Intellectual disability v5.265 NEUROG1 Achchuthan Shanmugasundram Phenotypes for gene: NEUROG1 were changed from Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469 to Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469
Intellectual disability v5.265 NEUROG1 Achchuthan Shanmugasundram Phenotypes for gene: NEUROG1 were changed from developmental delay; behavioural problems; cranial dysinnervation; absent corneal reflex to Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469
Intellectual disability v5.264 NEUROG1 Achchuthan Shanmugasundram reviewed gene: NEUROG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23419067, 26077850, 33439489, 36647078; Phenotypes: Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.93 SLC52A2 Sarah Leigh Phenotypes for gene: SLC52A2 were changed from Brown-Vialetto-Van Laere syndrome 2, 614707 to Brown-Vialetto-Van Laere syndrome 2, OMIM:614707; brown-Vialetto-van Laere syndrome 2, MONDO:0013867
Mitochondrial disorders v4.92 SLC52A2 Sarah Leigh Publications for gene: SLC52A2 were set to
Mitochondrial disorders v4.91 PLA2G6 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: PLA2G6.
Mitochondrial disorders v4.91 PLA2G6 Sarah Leigh Classified gene: PLA2G6 as Amber List (moderate evidence)
Mitochondrial disorders v4.91 PLA2G6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v4.91 PLA2G6 Sarah Leigh Gene: pla2g6 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.90 PLA2G6 Sarah Leigh edited their review of gene: PLA2G6: Added comment: Phospholipase A2 group VI (PLA2G6) is located in the mitochondrial membrane, in addition to the cytosol and endoplasmic reticulum (PMID: 32357911). Studies in PLA2G6 variant Drosophilia and PLA2G6 knock-down human fibrocytes suggest that PLA2G6 plays an important role in endolysosomal and mitochondrial function in disease (PMID: 30528460). PLA2G6 variants have been associated with Infantile neuroaxonal dystrophy 1, (OMIM:256600), Neurodegeneration with brain iron accumulation 2B (OMIM:610217) and Parkinson disease 14, autosomal recessive (OMIM:612953)(PMID: 35803092, 16783378, 30528460.; Changed rating: GREEN; Changed publications to: 32357911
Mitochondrial disorders v4.90 PLA2G6 Sarah Leigh Phenotypes for gene: PLA2G6 were changed from Infantile neuroaxonal dystrophy 1 256600; Neurodegeneration with brain iron accumulation 2B 610217; Parkinson disease 14, autosomal recessive 612953 to Infantile neuroaxonal dystrophy 1, OMIM:256600; neurodegeneration with brain iron accumulation 2A, MONDO:0024457; Neurodegeneration with brain iron accumulation 2B, OMIM:610217; neurodegeneration with brain iron accumulation 2B, MONDO:0012444; Parkinson disease 14, autosomal recessive, OMIM:612953; autosomal recessive Parkinson disease 14 MONDO:0013060
Mitochondrial disorders v4.89 PLA2G6 Sarah Leigh Publications for gene: PLA2G6 were set to 29903433; 25348461; 26001724; 26506412; 30528460; 16783378
Mitochondrial disorders v4.88 PLA2G6 Sarah Leigh Mode of inheritance for gene: PLA2G6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh changed review comment from: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :

16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.; to: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :

16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

This data has been submitted for publication

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh changed review comment from: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :
16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.; to: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :

16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh commented on gene: CRELD1: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :
16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.
Breast cancer pertinent cancer susceptibility v2.5 ATRIP Dmitrijs Rots reviewed gene: ATRIP: 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: 37592023; Phenotypes: Breast cancer; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Haematological malignancies cancer susceptibility v4.2 PTPN13 Dmitrijs Rots gene: PTPN13 was added
gene: PTPN13 was added to Haematological malignancies cancer susceptibility. Sources: Literature
Mode of inheritance for gene: PTPN13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPN13 were set to PMID: 35643866
Phenotypes for gene: PTPN13 were set to bone marrow failure and acute lymphoblastic leukemia
Review for gene: PTPN13 was set to AMBER
Added comment: PMID: 35643866 described two families with biallelic PTPN13 and bone marrow failure and acute lymphoblastic leukemia and some functional evidence. In gnomAD (under variant co-occurence) no rare truncating and strong missense in comp het or homozygous states.
Sources: Literature
Mitochondrial disorders v4.87 PLA2G6 Sarah Leigh Publications for gene: PLA2G6 were set to 29903433
Mitochondrial disorders v4.86 PITRM1 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: PITRM1.
Mitochondrial disorders v4.86 PITRM1 Sarah Leigh Classified gene: PITRM1 as Amber List (moderate evidence)
Mitochondrial disorders v4.86 PITRM1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v4.86 PITRM1 Sarah Leigh Gene: pitrm1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.85 PITRM1 Sarah Leigh commented on gene: PITRM1: The review article "Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration" (PMID:34356897) outlines the role of PITRM1 in normal mitochondrial function, it also presents the published evidence which demonstrates the consequences of variant PITRM1, in humans and functional studies.
Mitochondrial disorders v4.85 PITRM1 Sarah Leigh edited their review of gene: PITRM1: Changed publications to: 33835239, 34356897
Intellectual disability v5.264 CMIP Sarah Leigh reviewed gene: CMIP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v5.264 CMIP Sarah Leigh Classified gene: CMIP as Red List (low evidence)
Intellectual disability v5.264 CMIP Sarah Leigh Gene: cmip has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v3.30 UQCRB Arina Puzriakova Phenotypes for gene: UQCRB were changed from Mitochondrial complex III deficiency, nuclear type 3, OMIM:615158 to Mitochondrial complex III deficiency, nuclear type 3, OMIM:615158
Paediatric or syndromic cardiomyopathy v3.29 UQCRB Arina Puzriakova Phenotypes for gene: UQCRB were changed from Mitochondrial complex III deficiency, nuclear type 3, 615158 to Mitochondrial complex III deficiency, nuclear type 3, OMIM:615158
Intellectual disability v5.263 UQCRB Arina Puzriakova Phenotypes for gene: UQCRB were changed from Mitochondrial complex III deficiency, nuclear type 3, 615158 to Mitochondrial complex III deficiency, nuclear type 3, OMIM:615158
Fetal anomalies v3.108 UQCRB Arina Puzriakova Phenotypes for gene: UQCRB were changed from MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX III DEFICIENCY, UQCRB-RELATED to Mitochondrial complex III deficiency, nuclear type 3, OMIM:615158
Likely inborn error of metabolism v4.49 UQCRB Arina Puzriakova Phenotypes for gene: UQCRB were changed from Mitochondrial complex III deficiency, nuclear type 3, 615158; Mitochondrial Diseases; Complex III (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Mitochondrial complex III deficiency, nuclear type 3 615158; Isolated complex III deficiency to Mitochondrial complex III deficiency, nuclear type 3, OMIM:615158; Complex III (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Isolated complex III deficiency
Possible mitochondrial disorder - nuclear genes v3.49 UQCRB Arina Puzriakova Phenotypes for gene: UQCRB were changed from Mitochondrial complex III deficiency, nuclear type 3, 615158 to Mitochondrial complex III deficiency, nuclear type 3, OMIM:615158
Undiagnosed metabolic disorders v1.600 UQCRB Arina Puzriakova Phenotypes for gene: UQCRB were changed from Complex III (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Mitochondrial complex III deficiency, nuclear type 3 615158 to Mitochondrial complex III deficiency, nuclear type 3, OMIM:615158; Complex III (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits)
Mitochondrial disorder with complex III deficiency v2.3 UQCRB Arina Puzriakova Phenotypes for gene: UQCRB were changed from Mitochondrial complex III deficiency, nuclear type 3, 615158 to Mitochondrial complex III deficiency, nuclear type 3, OMIM:615158
Mitochondrial disorders v4.85 UQCRB Arina Puzriakova Phenotypes for gene: UQCRB were changed from Mitochondrial complex III deficiency, nuclear type 3, 615158 to Mitochondrial complex III deficiency, nuclear type 3, OMIM:615158
Mitochondrial disorders v4.84 UQCRB Arina Puzriakova Publications for gene: UQCRB were set to 12709789; 25446085; 23454382; 28604960
Skeletal dysplasia v4.16 PKDCC Arina Puzriakova Phenotypes for gene: PKDCC were changed from Rhizomelia; dysmorphism to Rhizomelic limb shortening with dysmorphic features, OMIM:618821
Intellectual disability v5.262 CMIP Sarah Leigh Publications for gene: CMIP were set to PMID: 22689534; 28504353
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh reviewed gene: CRELD1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh Classified gene: CRELD1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh Gene: creld1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.93 CRELD1 Sarah Leigh Publications for gene: CRELD1 were set to PMID 32437232
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Tag watchlist was removed from gene: ATP6V0C.
Tag Q3_23_promote_green tag was added to gene: ATP6V0C.
Tag Q3_23_NHS_review tag was added to gene: ATP6V0C.
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Classified gene: ATP6V0C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.92 ATP6V0C 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 review.
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Classified gene: ATP6V0C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.92 ATP6V0C 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 review.
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.91 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 24623842; 33190975; 35600075; 36074901; 37161035
Early onset or syndromic epilepsy v4.90 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Early onset or syndromic epilepsy v4.89 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Early onset or syndromic epilepsy v4.89 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Early onset or syndromic epilepsy v4.89 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy; Intellectual Disability; microcephaly to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Early onset or syndromic epilepsy v4.88 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 33190975; 33090716
Early onset or syndromic epilepsy v4.87 ATP6V0C Achchuthan Shanmugasundram reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 24623842, 33190975, 35600075, 36074901, 37161035; Phenotypes: Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.87 MAGI2 Zornitza Stark commented on gene: MAGI2: In addition, note the gene-disease relationship to epilepsy has been assessed as DISPUTED by ClinGen.
Early onset or syndromic epilepsy v4.87 CACNB4 Zornitza Stark reviewed gene: CACNB4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Epilepsy, juvenile myoclonic, susceptibility to, 6}, MIM# 607682, {Epilepsy, idiopathic generalized, susceptibility to, 9}, MIM#607682; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Classified gene: ATP6V0C as Amber List (moderate evidence)
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (17 unrelated cases) for this gene to be promoted to green rating in the next GMS review.
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (17 unrelated cases) for this gene to be promoted to green rating in the next GMS review.; to: Comment on list classification: There is sufficient evidence available (17 unrelated cases) for this gene to be promoted to green rating in the next GMS review.
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Classified gene: ATP6V0C as Amber List (moderate evidence)
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (17 unrelated cases) for this gene to be promoted to green rating in the next GMS review.
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Classified gene: ATP6V0C as Amber List (moderate evidence)
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (17 unrelated cases) for this gene to be promoted to green rating in the next GMS review.
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.261 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Tag watchlist was removed from gene: ATP6V0C.
Tag Q3_23_promote_green tag was added to gene: ATP6V0C.
Tag Q3_23_NHS_review tag was added to gene: ATP6V0C.
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 24623842; 33090716; 33190975; 36074901; 37161035
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy; Intellectual Disability; microcephaly to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 24623842; 33090716; 33190975; 36074901; 37161035
Intellectual disability v5.260 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 24623842; 33090716; 33190975; 36074901; 37161035
Intellectual disability v5.259 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 24623842; 33090716; 33190975; 36074901; 37161035
Intellectual disability v5.259 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 24623842; 33190975; 33090716; 36074901; 37161035
Intellectual disability v5.258 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 24623842; 33190975; 33090716; 36074901; 37161035
Intellectual disability v5.258 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 33190975; 33090716
Intellectual disability v5.257 ATP6V0C Achchuthan Shanmugasundram edited their review of gene: ATP6V0C: Changed publications to: 24623842, 33190975, 36074901, 37161035
Intellectual disability v5.257 ATP6V0C Achchuthan Shanmugasundram changed review comment from: 17 of 32 total patients had impaired intellectual development.; to: PMID:36074901 - 16 of 27 patients identified with monoallelic ATP6V0C variants, including a patient each from PMID:24623842 and PMID:33190975 had impaired intellectual development, while 21 patients had developmental delay.

PMID:37161035 - One of three patients identified with monoallelic ATP6V0C variant had impaired intellectual development and language delay, while another had developmental delay and speech delay.

This gene has been associated with relevant phenotypes in OMIM (MIM #620465) and Gene2Phenotype (with 'strong' rating in the DD panel).
Intellectual disability v5.257 ATP6V0C Achchuthan Shanmugasundram edited their review of gene: ATP6V0C: Changed publications to: 24623842, 33190975, 35600075, 36074901, 37161035
Intellectual disability v5.257 ATP6V0C Achchuthan Shanmugasundram reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 33190975, 35600075, 36074901, 37161035; Phenotypes: Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.56 SYT2 Achchuthan Shanmugasundram Classified gene: SYT2 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.56 SYT2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene to this panel (six unrelated cases and functional studies) and this gene should therefore be promoted to green rating in the next GMS review.
Hereditary neuropathy or pain disorder v3.56 SYT2 Achchuthan Shanmugasundram Gene: syt2 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.55 SYT2 Achchuthan Shanmugasundram Phenotypes for gene: SYT2 were changed from Myasthenic syndrome, congenital, 7, presynaptic to Myasthenic syndrome, congenital, 7A, presynaptic, and distal motor neuropathy, autosomal dominant, OMIM:616040
Hereditary neuropathy or pain disorder v3.54 SYT2 Achchuthan Shanmugasundram Publications for gene: SYT2 were set to 26519543; 30533528
Hereditary neuropathy or pain disorder v3.53 SYT2 Achchuthan Shanmugasundram Mode of inheritance for gene: SYT2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.52 SYT2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: SYT2.
Hereditary neuropathy or pain disorder v3.52 SYT2 Achchuthan Shanmugasundram reviewed gene: SYT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25192047, 26519543, 30533528, 33105646, 34037996; Phenotypes: Myasthenic syndrome, congenital, 7A, presynaptic, and distal motor neuropathy, autosomal dominant, OMIM:616040; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.52 DHTKD1 Achchuthan Shanmugasundram Classified gene: DHTKD1 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.52 DHTKD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating in the next GMS review.
Hereditary neuropathy or pain disorder v3.52 DHTKD1 Achchuthan Shanmugasundram Gene: dhtkd1 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.51 DHTKD1 Achchuthan Shanmugasundram Phenotypes for gene: DHTKD1 were changed from Charcot Marie Tooth disease, axonal, type 2Q, 615025; 2 aminoadipic 2 oxoadipic aciduria, 204750 to ?Charcot-Marie-Tooth disease, axonal, type 2Q, OMIM:615025
Hereditary neuropathy or pain disorder v3.50 DHTKD1 Achchuthan Shanmugasundram Publications for gene: DHTKD1 were set to
Hereditary neuropathy or pain disorder v3.49 DHTKD1 Achchuthan Shanmugasundram Mode of inheritance for gene: DHTKD1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.48 DHTKD1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: DHTKD1.
Hereditary neuropathy or pain disorder v3.48 DHTKD1 Achchuthan Shanmugasundram reviewed gene: DHTKD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23141294, 28902413, 29661920, 34571524; Phenotypes: ?Charcot-Marie-Tooth disease, axonal, type 2Q, OMIM:615025; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rhabdomyolysis and metabolic muscle disorders v3.28 COQ8A Achchuthan Shanmugasundram Classified gene: COQ8A as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.28 COQ8A Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.28 COQ8A Achchuthan Shanmugasundram Gene: coq8a has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.27 COQ8A Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: COQ8A.
Tag Q3_23_NHS_review tag was added to gene: COQ8A.
Rhabdomyolysis and metabolic muscle disorders v3.27 COQ8A Achchuthan Shanmugasundram gene: COQ8A was added
gene: COQ8A was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list,Expert Review
Mode of inheritance for gene: COQ8A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ8A were set to 26818466; 22036850; 18319074; 18319072; 32337771
Phenotypes for gene: COQ8A were set to Coenzyme Q10 deficiency, primary, 4, OMIM:612016
Review for gene: COQ8A was set to GREEN
Added comment: Coenzyme Q10 deficiency is a heterogeneous disease with multple causal genes, typically inherited in an autosomal recessive pattern (including COQ8A/ADCK3). Variants in COQ8A cause a juvenile-onset cerebellar ataxia with primary CoQ10 deficiency. Some patients display muscle weakness and exercise intolerance (typically with elevated serum lactate) early in the course of disease but it is not clear if this is associated with rhabdomyolysis although this may be plausible following physical exertion.

PMID:32337771 reported a cohort of 59 individuals with 44 pathogenic COQ8A variants and presenting with variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus.
Sources: Expert list, Expert Review
Rhabdomyolysis and metabolic muscle disorders v3.26 MT-CO1 Achchuthan Shanmugasundram Phenotypes for gene: MT-CO1 were changed from Leber hereditary optic neuropathy; Myoglobinuria to Leber hereditary optic neuropathy, MONDO:0010788; myoglobinuria, MONDO:0000866
Rhabdomyolysis and metabolic muscle disorders v3.25 MT-CO1 Achchuthan Shanmugasundram edited their review of gene: MT-CO1: Changed phenotypes to: Leber hereditary optic neuropathy, MONDO:0010788, myoglobinuria, MONDO:0000866
Rhabdomyolysis and metabolic muscle disorders v3.25 MT-CO2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: MT-CO2.
Tag Q3_23_NHS_review tag was added to gene: MT-CO2.
Rhabdomyolysis and metabolic muscle disorders v3.25 MT-CO2 Achchuthan Shanmugasundram Classified gene: MT-CO2 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.25 MT-CO2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.25 MT-CO2 Achchuthan Shanmugasundram Gene: mt-co2 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.24 MT-CO2 Achchuthan Shanmugasundram gene: MT-CO2 was added
gene: MT-CO2 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list,Expert Review
Mode of inheritance for gene gene: MT-CO2 was set to MITOCHONDRIAL
Publications for gene: MT-CO2 were set to 14733964; 23616164; 25929793; 28521807
Phenotypes for gene: MT-CO2 were set to Cytochrome oxidase deficiency; rhabdomyolysis, MONDO:0005290; myoglobinuria, MONDO:0000866
Review for gene: MT-CO2 was set to GREEN
Added comment: Sources: Expert list, Expert Review
Rhabdomyolysis and metabolic muscle disorders v3.23 MT-CO1 Achchuthan Shanmugasundram Classified gene: MT-CO1 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.23 MT-CO1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.23 MT-CO1 Achchuthan Shanmugasundram Gene: mt-co1 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.22 MT-CO1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: MT-CO1.
Tag Q3_23_NHS_review tag was added to gene: MT-CO1.
Rhabdomyolysis and metabolic muscle disorders v3.22 MT-CO1 Achchuthan Shanmugasundram gene: MT-CO1 was added
gene: MT-CO1 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list,Expert Review
Mode of inheritance for gene gene: MT-CO1 was set to MITOCHONDRIAL
Publications for gene: MT-CO1 were set to 10980727; 25929793
Phenotypes for gene: MT-CO1 were set to Leber hereditary optic neuropathy; Myoglobinuria
Review for gene: MT-CO1 was set to GREEN
Added comment: Sources: Expert list, Expert Review
Rhabdomyolysis and metabolic muscle disorders v3.21 COQ4 Achchuthan Shanmugasundram Classified gene: COQ4 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.21 COQ4 Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.21 COQ4 Achchuthan Shanmugasundram Gene: coq4 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.20 COQ4 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: COQ4.
Tag Q3_23_NHS_review tag was added to gene: COQ4.
Rhabdomyolysis and metabolic muscle disorders v3.20 COQ4 Achchuthan Shanmugasundram edited their review of gene: COQ4: Changed publications to: 28472853, 26185144, 25658047
Rhabdomyolysis and metabolic muscle disorders v3.20 COQ4 Achchuthan Shanmugasundram gene: COQ4 was added
gene: COQ4 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list,Expert Review
Mode of inheritance for gene: COQ4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: COQ4 were set to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Review for gene: COQ4 was set to GREEN
Added comment: Coenzyme Q10 deficiency is a heterogeneous disease with multple causal genes, typically inherited in an autosomal recessive pattern (including COQ4). Literature review revealed only one patient who had displayed lethal rhabdomyolysis but importantly this individual only harboured a single heterozygous c.483 G >C (p.E161D) variant in COQ4 (PMID: 28472853)
Sources: Expert list, Expert Review
Mitochondrial disorders v4.83 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Coenzyme Q10 deficiency, primary, 7, OMIM:616276 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Hereditary ataxia with onset in adulthood v4.20 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Adult-onset ataxia-spasticity spectrum disease; Hereditary spastic paraparesis, MONDO:0019064; Cerebellar ataxia, MONDO:0000437 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Likely inborn error of metabolism v4.48 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Coenzyme Q10 deficiency, primary, 7, OMIM:616276 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Hereditary ataxia with onset in adulthood v4.19 COQ4 Achchuthan Shanmugasundram edited their review of gene: COQ4: Changed phenotypes to: Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Mitochondrial disorders v4.83 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Coenzyme Q10 deficiency, primary, 7, OMIM:616276 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Likely inborn error of metabolism v4.48 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Coenzyme Q10 deficiency, primary, 7, OMIM:616276 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Mitochondrial disorders v4.83 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Coenzyme Q10 deficiency, primary, 7, OMIM:616276 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Likely inborn error of metabolism v4.48 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Coenzyme Q10 deficiency, primary, 7, OMIM:616276 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Mitochondrial disorders v4.83 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Coenzyme Q10 deficiency, primary, 7; Disorders of ubiquinone metabolism and biosynthesis to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Likely inborn error of metabolism v4.48 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Coenzyme Q10 deficiency, primary, 7, OMIM:616276 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Likely inborn error of metabolism v4.48 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Coenzyme Q10 deficiency, primary, 7, OMIM:616276 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Likely inborn error of metabolism v4.47 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Coenzyme Q10 deficiency, primary, 7, OMIM:616276 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Likely inborn error of metabolism v4.47 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Disorders of CoQ10 biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of ubiquinone metabolism and biosynthesis; Coenzyme Q10 deficiency, primary, 7 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Undiagnosed metabolic disorders v1.599 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Disorders of CoQ10 biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Coenzyme Q10 deficiency, primary, 7; Disorders of ubiquinone metabolism and biosynthesis to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Adult onset hereditary spastic paraplegia v3.17 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Adult-onset ataxia-spasticity spectrum disease; Hereditary spastic paraparesis, MONDO:0019064; Cerebellar ataxia, MONDO:0000437 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Adult onset hereditary spastic paraplegia v3.16 COQ4 Achchuthan Shanmugasundram edited their review of gene: COQ4: Changed phenotypes to: Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Ataxia and cerebellar anomalies - narrow panel v4.30 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Childhood-onset spinocerebellar ataxia; Adult-onset ataxia-spasticity spectrum disease; Hereditary spastic paraparesis, MONDO:0019064; Cerebellar ataxia, MONDO:0000437 to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Ataxia and cerebellar anomalies - narrow panel v4.29 COQ4 Achchuthan Shanmugasundram edited their review of gene: COQ4: Changed phenotypes to: Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Acute rhabdomyolysis v1.13 PHKB Achchuthan Shanmugasundram Classified gene: PHKB as Green List (high evidence)
Acute rhabdomyolysis v1.13 PHKB Achchuthan Shanmugasundram Added comment: Comment on list classification: PHKB gene was demoted to Red in 'Rhabdomyolysis and metabolic muscle disorders' panel (https://panelapp.genomicsengland.co.uk/panels/66/gene/PHKB/) in agreement with the NHS Genomic Medicine Service. Hence, we propose that this gene should be reviewed for demotion to red in this panel.
Acute rhabdomyolysis v1.13 PHKB Achchuthan Shanmugasundram Gene: phkb has been classified as Green List (High Evidence).
Acute rhabdomyolysis v1.12 PHKB Achchuthan Shanmugasundram Tag Q3_23_expert_review tag was added to gene: PHKB.
Tag Q3_23_demote_red tag was added to gene: PHKB.
Acute rhabdomyolysis v1.12 PHKB Achchuthan Shanmugasundram reviewed gene: PHKB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Phosphorylase kinase deficiency of liver and muscle, autosomal recessive, OMIM:261750; Mode of inheritance: None
Possible mitochondrial disorder - nuclear genes v3.48 COX11 Hannah Knight reviewed gene: COX11: Rating: AMBER; Mode of pathogenicity: None; Publications: 36030551; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 23; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.48 COX5A Hannah Knight reviewed gene: COX5A: Rating: AMBER; Mode of pathogenicity: None; Publications: 35246835; Phenotypes: ?Mitochondrial complex IV deficiency, nuclear type 20; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v3.19 CHKB Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.; to: Comment on list classification: This gene is proposed for promotion to green rating as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.19 OBSCN Achchuthan Shanmugasundram Phenotypes for gene: OBSCN were changed from {Rhabdomyolysis, susceptibility to, 1}, OMIM:620235 to {Rhabdomyolysis, susceptibility to, 1}, OMIM:620235
Rhabdomyolysis and metabolic muscle disorders v3.19 OBSCN Achchuthan Shanmugasundram Phenotypes for gene: OBSCN were changed from to {Rhabdomyolysis, susceptibility to, 1}, OMIM:620235
Rhabdomyolysis and metabolic muscle disorders v3.18 OBSCN Achchuthan Shanmugasundram Tag watchlist was removed from gene: OBSCN.
Tag Q3_23_promote_green tag was added to gene: OBSCN.
Tag Q3_23_NHS_review tag was added to gene: OBSCN.
Rhabdomyolysis and metabolic muscle disorders v3.18 OBSCN Achchuthan Shanmugasundram Deleted their comment
Rhabdomyolysis and metabolic muscle disorders v3.18 OBSCN Achchuthan Shanmugasundram Classified gene: OBSCN as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.18 OBSCN Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.18 OBSCN Achchuthan Shanmugasundram Gene: obscn has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.18 OBSCN Achchuthan Shanmugasundram Classified gene: OBSCN as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.18 OBSCN Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.18 OBSCN Achchuthan Shanmugasundram Gene: obscn has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.17 OBSCN Achchuthan Shanmugasundram Mode of inheritance for gene: OBSCN was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v3.16 OBSCN Achchuthan Shanmugasundram Mode of inheritance for gene: OBSCN was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v3.16 OBSCN Achchuthan Shanmugasundram Mode of inheritance for gene: OBSCN was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v3.15 OBSCN Achchuthan Shanmugasundram Publications for gene: OBSCN were set to 18477606
Rhabdomyolysis and metabolic muscle disorders v3.14 OBSCN Achchuthan Shanmugasundram reviewed gene: OBSCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 34957489; Phenotypes: {Rhabdomyolysis, susceptibility to, 1}, OMIM:620235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v3.14 FLAD1 Achchuthan Shanmugasundram Deleted their comment
Rhabdomyolysis and metabolic muscle disorders v3.14 FLAD1 Achchuthan Shanmugasundram Classified gene: FLAD1 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.14 FLAD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.14 FLAD1 Achchuthan Shanmugasundram Gene: flad1 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.14 FLAD1 Achchuthan Shanmugasundram Classified gene: FLAD1 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.14 FLAD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.14 FLAD1 Achchuthan Shanmugasundram Gene: flad1 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.13 FLAD1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: FLAD1.
Tag Q3_23_NHS_review tag was added to gene: FLAD1.
Rhabdomyolysis and metabolic muscle disorders v3.13 FLAD1 Achchuthan Shanmugasundram gene: FLAD1 was added
gene: FLAD1 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list,Expert Review
Mode of inheritance for gene: FLAD1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FLAD1 were set to Lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiency, OMIM:255100
Review for gene: FLAD1 was set to GREEN
Added comment: FLAD1 gene encodes flavin adenine dinucleotide synthetase enzyme and it has been associated with lipid storage myopathy in OMIM (MIM #255100).

This gene also has green rating in Rhabdomyolysis and Metabolic Myopathy panel from PanelApp Australia (https://panelapp.agha.umccr.org/panels/3084/gene/FLAD1/) based on the evidence of more than 10 families reported in literature.
Sources: Expert list, Expert Review
Rhabdomyolysis and metabolic muscle disorders v3.12 DGUOK Achchuthan Shanmugasundram Classified gene: DGUOK as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.12 DGUOK Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.12 DGUOK Achchuthan Shanmugasundram Gene: dguok has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.11 DGUOK Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: DGUOK.
Tag Q3_23_NHS_review tag was added to gene: DGUOK.
Rhabdomyolysis and metabolic muscle disorders v3.11 DGUOK Achchuthan Shanmugasundram gene: DGUOK was added
gene: DGUOK was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list,Expert Review
Mode of inheritance for gene: DGUOK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DGUOK were set to Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), OMIM:251880; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, OMIM:617070
Review for gene: DGUOK was set to GREEN
Added comment: DGUOK gene encodes mitochondrial deoxyguanosine kinase enzyme. This gene is associated with relevant phebnotypes in OMIM (MIMs #251880 & #617070). Mitochondrial myopathy and muscle weaknesses are recorded as clinical manifestations of Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 (MIM #617070) in OMIM.
Sources: Expert list, Expert Review
Rhabdomyolysis and metabolic muscle disorders v3.10 CHKB Achchuthan Shanmugasundram Classified gene: CHKB as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.10 CHKB Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.10 CHKB Achchuthan Shanmugasundram Gene: chkb has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v3.9 CHKB Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: CHKB.
Tag Q3_23_NHS_review tag was added to gene: CHKB.
Rhabdomyolysis and metabolic muscle disorders v3.9 CHKB Achchuthan Shanmugasundram gene: CHKB was added
gene: CHKB was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert list,Expert Review
Mode of inheritance for gene: CHKB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHKB were set to 37011121
Phenotypes for gene: CHKB were set to Muscular dystrophy, congenital, megaconial type, OMIM:602541
Review for gene: CHKB was set to GREEN
Added comment: CHKB encodes choline kinase beta enzyme and it has been associated with congenital muscular dystrophy in OMIM (MIM #602541).

PMID:37011121 - 44 cases with biallelic CHKB variants had congenital muscular dystrophy and 3 cases had limb-girdle muscular dystrophy. Of these 3 cases with LGMD, two had presented with adolescent- or adult-onset rhabdomyolysis.
Sources: Expert list, Expert Review
Rhabdomyolysis and metabolic muscle disorders v3.8 AMPD1 Achchuthan Shanmugasundram Tag Q3_23_NHS_review tag was added to gene: AMPD1.
Rhabdomyolysis and metabolic muscle disorders v3.8 AMPD1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: AMPD1.
Rhabdomyolysis and metabolic muscle disorders v3.8 AMPD1 Achchuthan Shanmugasundram Classified gene: AMPD1 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v3.8 AMPD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by Natalie Bibb and Andrew Swale, this gene is proposed for promotion to green as it is already green on the acute rhabdomyolysis panel (R419, https://panelapp.genomicsengland.co.uk/panels/1141/) based on recommendation by the NHS Genomic Medicine Service.
Rhabdomyolysis and metabolic muscle disorders v3.8 AMPD1 Achchuthan Shanmugasundram Gene: ampd1 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v2.30 TEK Arina Puzriakova Phenotypes for gene: TEK were changed from Venous malformations, multiple cutaneous and mucosal, 600195 to Venous malformations, multiple cutaneous and mucosal, OMIM:600195; Unifocal and multifocal sporadic venous malformations; Blue rubber bleb naevus
Mosaic skin disorders - deep sequencing v2.29 TEK Arina Puzriakova Publications for gene: TEK were set to 27519652
Rhabdomyolysis and metabolic muscle disorders v3.7 AMPD1 Achchuthan Shanmugasundram reviewed gene: AMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy due to myoadenylate deaminase deficiency, OMIM:615511; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mosaic skin disorders - deep sequencing v2.28 TEK Arina Puzriakova Mode of pathogenicity for gene: TEK 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
Mosaic skin disorders - deep sequencing v2.27 TEK Arina Puzriakova Tag somatic tag was added to gene: TEK.
Tag Q3_23_promote_green tag was added to gene: TEK.
Tag Q3_23_NHS_review tag was added to gene: TEK.
Mosaic skin disorders - deep sequencing v2.27 TEK Arina Puzriakova Classified gene: TEK as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.27 TEK Arina Puzriakova Added comment: Comment on list classification: Multiple cases of sporadic vascular malformations due to cutaneous mosaicism of a TEK variant (PMID: 19079259; 30677207; 34850385; 35460567; 35740480; 36924216). Different variants reported but the L914F substitution is most common and as are double variants found in cis. Somatic variants may not be picked up via other panels for the phenotype (R326) and therefore this gene should be promoted to Green at then next GMS panel update.
Mosaic skin disorders - deep sequencing v2.27 TEK Arina Puzriakova Gene: tek has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.48 MRM2 Hannah Knight reviewed gene: MRM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 36002240; Phenotypes: ?Mitochondrial DNA depletion syndrome 17; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.48 PTCD3 Hannah Knight reviewed gene: PTCD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36450274; Phenotypes: Combined oxidative phosphorylation deficiency 51; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.87 CRELD1 Sarah Leigh Phenotypes for gene: CRELD1 were changed from Developmental epileptic encephalopathy; intractable seizures; global developmental delay and cognitive delay; treatment resistant epileptic seizures; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; acute respiratory distress; submucosal cleft palate to Atrioventricular septal defect, partial, with heterotaxy syndrome, OMIM:606217; {Atrioventricular septal defect, susceptibility to, 2}, OMIM:606217; atrioventricular septal defect, susceptibility to, 2, MONDO:0011650
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.22 HMGCR Sarah Leigh Tag Q3_23_promote_green tag was added to gene: HMGCR.
Tag Q3_23_MOI tag was added to gene: HMGCR.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.22 HMGCR Sarah Leigh edited their review of gene: HMGCR: Added comment: HMGCR variants have been associated with Muscular dystrophy, limb-girdle, autosomal recessive 28 (OMIM:620375), but with a phenotype in Gen2Phen. PMIDs 37167966; 36745799 report seven HMGCR variants in four unrelated cases. Segregation of the variants and the condition was seen all of the families and in vitro studies revealed that the variant protein had a reduced activity (PMID: 36745799).; Changed rating: GREEN
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.22 HMGCR Sarah Leigh Classified gene: HMGCR as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.22 HMGCR Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.22 HMGCR Sarah Leigh Gene: hmgcr has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.21 HMGCR Sarah Leigh Phenotypes for gene: HMGCR were changed from Autosomal recessive limb-girdle muscular dystrophy-28; muscle weakness; myopathy to Muscular dystrophy, limb-girdle, autosomal recessive 28, OMIM:620375
Mosaic skin disorders - deep sequencing v2.26 PTCH1 Arina Puzriakova Publications for gene: PTCH1 were set to
Mosaic skin disorders - deep sequencing v2.25 PTCH1 Arina Puzriakova Classified gene: PTCH1 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.25 PTCH1 Arina Puzriakova Added comment: Comment on list classification: New gene on this panel added by Tom Cullup (GOSH). Multiple cases have been reported where linear and segmental basal cell carcinomas developed due to cutaneous mosaicism of a heterozygous variant in the PTCH1 gene (PMID: 23746055; 27658957; 30520020; 32298489; 35235545; 36002246). These variants may not be picked up via other panels for the phenotype and therefore this gene should be promoted to Green at then next GMS panel update.
Mosaic skin disorders - deep sequencing v2.25 PTCH1 Arina Puzriakova Gene: ptch1 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.48 ATP5E Hannah Knight reviewed gene: ATP5E: Rating: GREEN; Mode of pathogenicity: None; Publications: 34954817; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.82 ATP5B Hannah Knight reviewed gene: ATP5B: Rating: AMBER; Mode of pathogenicity: None; Publications: 36239646, 36860166; Phenotypes: Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder - nuclear genes v3.48 ATP5B Hannah Knight reviewed gene: ATP5B: Rating: AMBER; Mode of pathogenicity: None; Publications: 36239646, 36860166; Phenotypes: Hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v2.24 PTCH1 Arina Puzriakova Tag mosaicism tag was added to gene: PTCH1.
Tag somatic tag was added to gene: PTCH1.
Mosaic skin disorders - deep sequencing v2.24 PTCH1 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: PTCH1.
Tag Q3_23_NHS_review tag was added to gene: PTCH1.
Mosaic skin disorders - deep sequencing v2.24 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Gorlin syndrome / basal cell naevus syndrome to Basal cell nevus syndrome 1, OMIM:109400; Basal cell carcinoma, somatic, OMIM:605462; Gorlin syndrome
Cerebral vascular malformations v3.5 PIK3CA Sarah Leigh edited their review of gene: PIK3CA: Added comment: Somatic PIK3CA variants are associated with Cerebral cavernous malformations 4, somatic, OMIM:619538. At least three somatic PIK3CA variants have been reported (PMID: 34496175).; Changed rating: RED
Genodermatoses with malignancies v1.10 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Basal cell nevus syndrome, 109400; Basal cell carcinoma, somatic, 605462; Holoprosencephaly-7, 610828; Nevoid Basal Cell Carcinoma Syndrome (aka Gorlin syndrome); Basal Cell Nevus Syndrome (aka Gorlin syndrome); Basal cell nevus syndrome; Nevoid Basal Cell Carcinoma Syndrome; (originally on Gorlin syndrome gene panel) to Basal cell nevus syndrome 1, OMIM:109400; Basal cell carcinoma, somatic, OMIM:605462; Gorlin syndrome
Childhood solid tumours v4.7 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Basal cell nevus syndrome 1, OMIM:109400; Gorlin syndrome to Basal cell nevus syndrome 1, OMIM:109400; Gorlin syndrome
Adult solid tumours for rare disease v1.37 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Gorlin syndrome, BCC to Basal cell nevus syndrome 1, OMIM:109400; Gorlin syndrome
Adult solid tumours cancer susceptibility v2.25 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Gorlin syndrome, BCC to Basal cell nevus syndrome 1, OMIM:109400; Gorlin syndrome
Childhood solid tumours cancer susceptibility v1.25 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Gorlin syndrome to Basal cell nevus syndrome 1, OMIM:109400; Gorlin syndrome
Bilateral congenital or childhood onset cataracts v4.3 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from BASAL CELL NEVUS SYNDROME to Basal cell nevus syndrome 1, OMIM:109400
Childhood solid tumours v4.6 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from 109400; Gorlin syndrome to Basal cell nevus syndrome 1, OMIM:109400; Gorlin syndrome
Intellectual disability v5.257 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Basal cell nevus syndrome, 109400Basal cell carcinoma, somatic, 605462Holoprosencephaly-7, 610828; HOLOPROSENCEPHALY-7 to Holoprosencephaly 7, OMIM:610828
Early onset or syndromic epilepsy v4.86 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Basal cell nevus syndrome, 109400; Holoprosencephaly 7, 610828; Basal cell carcinoma, somatic, 605462 to Holoprosencephaly 7, OMIM:610828
Clefting v4.94 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from BASAL CELL NEVUS SYNDROME; BCNS, HOLOPROSENCEPHALY 7; HPE7 to Holoprosencephaly 7, OMIM:610828; Basal cell nevus syndrome 1, OMIM:109400
Fetal anomalies v3.107 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from HOLOPROSENCEPHALY-7; BASAL CELL NEVUS SYNDROME to Holoprosencephaly 7, OMIM:610828
Cerebral vascular malformations v3.5 PIK3CA Sarah Leigh Added comment: Comment on mode of inheritance: Somatic PIK3CA variant are associated with Cerebral cavernous malformations 4, somatic, OMIM:619538.
Cerebral vascular malformations v3.5 PIK3CA Sarah Leigh Mode of inheritance for gene: PIK3CA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Holoprosencephaly v4.2 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Holoprosencephaly-7; Holoprosencephaly; Holoprosencephaly 7, 610828 to Holoprosencephaly 7, OMIM:610828
Pituitary hormone deficiency v3.2 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Holoprosencephaly 7 (610828) to Holoprosencephaly 7, OMIM:610828
Cerebral vascular malformations v3.4 PIK3CA Sarah Leigh Tag somatic tag was added to gene: PIK3CA.
Cerebral vascular malformations v3.4 PIK3CA Sarah Leigh Phenotypes for gene: PIK3CA were changed from Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, 602501 ; Cerebral Malformation Disorders; Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome; Congenital Lipomatous Overgrowth, Vascular Malformations, and Epidermal Nevi; Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic to Cerebral cavernous malformations 4, somatic, OMIM:619538
Cerebral vascular malformations v3.3 PIK3CA Sarah Leigh Publications for gene: PIK3CA were set to
Cerebral vascular malformations v3.2 PIK3CA Sarah Leigh Mode of inheritance for gene: PIK3CA was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Parkinson Disease and Complex Parkinsonism v1.120 PDGFB Sarah Leigh Publications for gene: PDGFB were set to 23913003
Childhood onset dystonia, chorea or related movement disorder v3.48 PDGFB Sarah Leigh edited their review of gene: PDGFB: Added comment: PDGFB variants are associated with Basal ganglia calcification, idiopathic, 5 (OMIM:615483). No phenotype has been associated with PDGFB in Gen2Phen. Although the age of onset for OMIM:615483 is in adulthood, PMID: 23913003 reports four unrelated cases where the age of onset is listed as childhood or 10 years of age.; Changed rating: GREEN
Parkinson Disease and Complex Parkinsonism v1.119 PDGFB Sarah Leigh Classified gene: PDGFB as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.119 PDGFB Sarah Leigh Gene: pdgfb has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.118 PDGFB Sarah Leigh Deleted their comment
Parkinson Disease and Complex Parkinsonism v1.118 PDGFB Sarah Leigh edited their review of gene: PDGFB: Added comment: PDGFB variants are associated with Basal ganglia calcification, idiopathic, 5 (OMIM:615483), which includes Parkinsonism. No phenotype has been associated with PDGFB in Gen2Phen. PMID: 23913003 reports three unrelated cases of OMIM:615483 who have Parkinsonism, and PMID: 35747618 notes Parkinsonism in the proband's paternal grandmother and great grandmother, however, no genetic analysis was possible for these deceased family members.; Changed rating: GREEN
Parkinson Disease and Complex Parkinsonism v1.118 PDGFB Sarah Leigh Classified gene: PDGFB as Amber List (moderate evidence)
Parkinson Disease and Complex Parkinsonism v1.118 PDGFB Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Parkinson Disease and Complex Parkinsonism v1.118 PDGFB Sarah Leigh Gene: pdgfb has been classified as Amber List (Moderate Evidence).
Parkinson Disease and Complex Parkinsonism v1.117 PDGFB Sarah Leigh Phenotypes for gene: PDGFB were changed from Basal ganglia calcification, idiopathic, 5, MIM# 615483 to Basal ganglia calcification, idiopathic, 5, OMIM:615483; basal ganglia calcification, idiopathic, 5, MONDO:0014204
Childhood onset dystonia, chorea or related movement disorder v3.48 PDGFB Sarah Leigh Phenotypes for gene: PDGFB were changed from Basal ganglia calcification, idiopathic, 5, OMIM:615483 to Basal ganglia calcification, idiopathic, 5, OMIM:615483; basal ganglia calcification, idiopathic, 5, MONDO:0014204
Childhood onset dystonia, chorea or related movement disorder v3.47 PDGFB Sarah Leigh Publications for gene: PDGFB were set to 26129893; 23913003; 30952898; 30609140; 35747618
Childhood onset dystonia, chorea or related movement disorder v3.46 PDGFB Sarah Leigh Publications for gene: PDGFB were set to 26129893; 23913003; 30952898; 30609140
Childhood onset dystonia, chorea or related movement disorder v3.45 PDGFB Sarah Leigh Phenotypes for gene: PDGFB were changed from Basal ganglia calcification, idiopathic, 5, 615483 to Basal ganglia calcification, idiopathic, 5, OMIM:615483
Childhood onset dystonia, chorea or related movement disorder v3.44 PDGFB Sarah Leigh Deleted their comment
Childhood onset dystonia, chorea or related movement disorder v3.44 PDGFB Sarah Leigh Added comment: Comment on publications: ;23913003;30952898;30609140
Childhood onset dystonia, chorea or related movement disorder v3.44 PDGFB Sarah Leigh Publications for gene: PDGFB were set to 26129893
Childhood onset dystonia, chorea or related movement disorder v3.43 OCLN Sarah Leigh Tag Q3_23_expert_review tag was added to gene: OCLN.
Tag Q3_23_demote_red tag was added to gene: OCLN.
Childhood onset dystonia, chorea or related movement disorder v3.43 OCLN Sarah Leigh edited their review of gene: OCLN: Added comment: It would appear that there are no published reports of dystonia, chorea or related movement disorder in cases carrying OCLN variants (PMID:20727516;34704946;34573918;28386946).; Changed rating: RED; Changed publications to: 20727516, 34704946, 34573918, 28386946
Childhood onset dystonia, chorea or related movement disorder v3.43 OCLN Sarah Leigh Classified gene: OCLN as Green List (high evidence)
Childhood onset dystonia, chorea or related movement disorder v3.43 OCLN Sarah Leigh Added comment: Comment on list classification: To date, there are no reports of dystonia, chorea or other movement disorders associated with OCLN variants (PMID: 20727516;34704946;34573918;28386946). Therefore this gene should not be green on this panel.
Childhood onset dystonia, chorea or related movement disorder v3.43 OCLN Sarah Leigh Gene: ocln has been classified as Green List (High Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.42 KCNQ2 Sarah Leigh Classified gene: KCNQ2 as Green List (high evidence)
Childhood onset dystonia, chorea or related movement disorder v3.42 KCNQ2 Sarah Leigh Added comment: Comment on list classification: There is only one case (PMID:12742592), of dystonia in a patient carrying a KCNQ2 variant. To date, there are no reports of relevant chorea or other movement disorders associated with KCNQ2 variants (PMID: 22275249;22926866;23621294;31418850;35780567;33794528). Therefore this gene should not be green on this panel.
Childhood onset dystonia, chorea or related movement disorder v3.42 KCNQ2 Sarah Leigh Gene: kcnq2 has been classified as Green List (High Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.41 KCNQ2 Sarah Leigh Tag Q3_23_expert_review tag was added to gene: KCNQ2.
Childhood onset dystonia, chorea or related movement disorder v3.41 KCNQ2 Sarah Leigh Tag Q3_23_demote_red tag was added to gene: KCNQ2.
Childhood onset dystonia, chorea or related movement disorder v3.41 KCNQ2 Sarah Leigh reviewed gene: KCNQ2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood onset dystonia, chorea or related movement disorder v3.41 KCNQ2 Sarah Leigh Publications for gene: KCNQ2 were set to 12742592
Childhood onset dystonia, chorea or related movement disorder v3.40 KCNQ2 Sarah Leigh Phenotypes for gene: KCNQ2 were changed from Myokymia, 121200; Dystonia to Developmental and epileptic encephalopathy 7, OMIM:613720; developmental and epileptic encephalopathy, 7, MONDO:0013387; Myokymia, OMIM:121200; Seizures, benign neonatal, 1, OMIM:121200; seizures, benign familial neonatal, 1, MONDO:0007365
Childhood onset dystonia, chorea or related movement disorder v3.39 KCNQ2 Sarah Leigh Publications for gene: KCNQ2 were set to
White matter disorders and cerebral calcification - narrow panel v3.16 HPDL Sarah Leigh Tag gene-checked was removed from gene: HPDL.
White matter disorders and cerebral calcification - narrow panel v3.16 HPDL Sarah Leigh Deleted their comment
White matter disorders and cerebral calcification - narrow panel v3.16 HPDL Sarah Leigh edited their review of gene: HPDL: Added comment: Biallelic HPDL variants have been associated with Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (OMIM:619026) and Spastic paraplegia 83, autosomal recessive (OMIM:619027) in OMIM and as a Strong gene for HPDL Neurodegenerative Disease in Gen2Phen.
PMIDs 32707086 and 33188300 report white matter changes in 16/28 individuals from 9/18 families where MRI assessments were available.; Changed rating: GREEN
White matter disorders and cerebral calcification - narrow panel v3.16 HPDL Sarah Leigh Classified gene: HPDL as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v3.16 HPDL Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be Green at the next major review.
White matter disorders and cerebral calcification - narrow panel v3.16 HPDL Sarah Leigh Gene: hpdl has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v3.15 HPDL Sarah Leigh Entity copied from Severe microcephaly v4.28
White matter disorders and cerebral calcification - narrow panel v3.15 HPDL Sarah Leigh gene: HPDL was added
gene: HPDL was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature,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; 33188300
Phenotypes for gene: HPDL were set to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613
Childhood onset hereditary spastic paraplegia v4.18 HPDL Sarah Leigh Deleted their comment
Childhood onset hereditary spastic paraplegia v4.18 HPDL Sarah Leigh Deleted their comment
Monogenic hearing loss v4.14 GOSR2 Achchuthan Shanmugasundram gene: GOSR2 was added
gene: GOSR2 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: GOSR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOSR2 were set to 37074134
Phenotypes for gene: GOSR2 were set to hearing loss, autosomal recessive, MONDO:0019588
Review for gene: GOSR2 was set to RED
Added comment: Four children from two sibships from an extended consanguineous Palestinian family were reported with congenital profound hearing loss, whereas the parents of both sibships are first cousins with normal hearing. The families reported occasional febrile seizures in infancy for each of the deaf children, but these did not persist into adolescence. These affected children were identified with autosomal recessive GOSR2 variant, c.1A > C, p.Met1Leu. This variant appeared once in the gnomAD database, as a heterozygote, and not in any of ~2000 in-house controls of Palestinian ancestry.

All previously reported cases with biallelic GOSR2 variants had normal hearing and hence the differences in translation efficiency due to the effect of this variant may be responsible for this hearing loss phenotype (PMID:37074134).
Sources: Literature
Intellectual disability v5.256 NEUROG1 Julia Baptista gene: NEUROG1 was added
gene: NEUROG1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: NEUROG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEUROG1 were set to 36647078; 33439489; 23419067; 26077850
Phenotypes for gene: NEUROG1 were set to developmental delay; behavioural problems; cranial dysinnervation; absent corneal reflex
Review for gene: NEUROG1 was set to GREEN
Added comment: Five affected individuals from four independently reported families (Middle Eastern, Portuguese, Indian and Turkish backgrounds) with biallelic microdeletion, missense, nonsense or frameshift variants.

Affected individuals present at birth or in early infancy with corneal opacities due to absent blinking, sensorineural deafness associated with hypoplastic or malformed cochlea and hypoplasia or agenesis of CN VIII was reported. Developmental delay, poor speech, autistic behavior and dysmorphic facial features were also present.
Sources: Literature
Severe microcephaly v4.28 ATP6V0C Julia Baptista reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 36074901; Phenotypes: Epilepsy, Intellectual Disability, Microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.256 ATP6V0C Julia Baptista reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 36074901; Phenotypes: Epilepsy, Intellectual Disability, Microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.85 ATP6V0C Julia Baptista reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 36074901; Phenotypes: Epilepsy, Intellectual Disability, Microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.20 HMGCR Julia Baptista gene: HMGCR was added
gene: HMGCR was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Expert Review,Literature
Mode of inheritance for gene: HMGCR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMGCR were set to 37167966; 36745799
Phenotypes for gene: HMGCR were set to Autosomal recessive limb-girdle muscular dystrophy-28; muscle weakness; myopathy
Review for gene: HMGCR was set to GREEN
Added comment: Several families reported and OMIM entry now available.

Morales-Rosado et al. (2023) reported 9 patients from 5 unrelated families with LGMDR28. Symptoms included hypotonia, delayed motor milestones, and axial and neck muscle weakness. Progressive proximal muscle weakness of the upper and lower limbs, waddling gait, muscle atrophy, and increased serum creatine kinase were also described. Biallelic pathogenic variants identified by exome sequencing including missense, in-frame deletion and splice site.

Yogev et al (2023) reported 6 affected members of a large consanguineous Bedouin kindred with LGMDR28. In vitro functional studies of the missense variant supported a partial loss of function effect.
Sources: Expert Review, Literature
Cytopenia - NOT Fanconi anaemia v3.2 RAP1B Hannah Knight reviewed gene: RAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 35451551; Phenotypes: Syndromic thrombocytopenia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cytopenia - NOT Fanconi anaemia v3.2 TCIRG1 Hannah Knight gene: TCIRG1 was added
gene: TCIRG1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature
Mode of inheritance for gene: TCIRG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCIRG1 were set to 24753205
Phenotypes for gene: TCIRG1 were set to Congenital neutropenia
Penetrance for gene: TCIRG1 were set to unknown
Review for gene: TCIRG1 was set to AMBER
Added comment: A specific, novel variant in TCIRG1 (R736S) identified as the probable cause for SCN in a large multigenerational family through exome sequencing (Makaryan et al. 2014 - PMID 24753205)
In 2022, a new family identified in Taiwan to have a variant affecting the same amino acid (R736C) - https://doi.org/10.1182/blood-2022-159214
Sources: Literature
Stickler syndrome v4.1 LRP2 Dmitrijs Rots reviewed gene: LRP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v4.15 UBA2 Tracy Lester reviewed gene: UBA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder - nuclear genes v3.48 QARS Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: QARS.
Possible mitochondrial disorder - nuclear genes v3.48 QARS Achchuthan Shanmugasundram Classified gene: QARS as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.48 QARS Achchuthan Shanmugasundram Added comment: Comment on list classification: QARS encodes t-RNA synthetase and it should be included in this panel with green rating in line with other t-RNA synthetases.
Possible mitochondrial disorder - nuclear genes v3.48 QARS Achchuthan Shanmugasundram Gene: qars has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.47 QARS Achchuthan Shanmugasundram Publications for gene: QARS were set to
Possible mitochondrial disorder - nuclear genes v3.46 QARS Achchuthan Shanmugasundram reviewed gene: QARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, OMIM:615760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.256 DNAH14 Sarah Leigh Publications for gene: DNAH14 were set to 35438214
Intellectual disability v5.256 DNAH14 Sarah Leigh Classified gene: DNAH14 as Red List (low evidence)
Intellectual disability v5.256 DNAH14 Sarah Leigh Gene: dnah14 has been classified as Red List (Low Evidence).
Intellectual disability v5.255 DNAH14 Sarah Leigh reviewed gene: DNAH14: Rating: RED; Mode of pathogenicity: None; Publications: 26036949, 30125339, 26636390, 32848021; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.82 QARS Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, QARS should be included in this panel with green rating in the next GMS review in line with other t-RNA synthetases.; to: Comment on list classification: As reviewed by Zornitza Stark, QARS should be included in this panel with green rating in line with other t-RNA synthetases.
Mitochondrial disorders v4.82 QARS Achchuthan Shanmugasundram Deleted their comment
Mitochondrial disorders v4.82 QARS Achchuthan Shanmugasundram Classified gene: QARS as Amber List (moderate evidence)
Mitochondrial disorders v4.82 QARS Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, QARS should be included in this panel with green rating in the next GMS review in line with other t-RNA synthetases.
Mitochondrial disorders v4.82 QARS Achchuthan Shanmugasundram Gene: qars has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.82 QARS Achchuthan Shanmugasundram Classified gene: QARS as Amber List (moderate evidence)
Mitochondrial disorders v4.82 QARS Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, QARS should be included in this panel with green rating in the next GMS review in line with other t-RNA synthetases.
Mitochondrial disorders v4.82 QARS Achchuthan Shanmugasundram Gene: qars has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.81 QARS Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: QARS.
Mitochondrial disorders v4.81 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; Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Mitochondrial disorders v4.80 QARS Achchuthan Shanmugasundram Publications for gene: QARS were set to
Mitochondrial disorders v4.79 QARS Achchuthan Shanmugasundram Mode of inheritance for gene: QARS was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.78 QARS Achchuthan Shanmugasundram reviewed gene: QARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, OMIM:615760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.48 SPTAN1 Sarah Leigh Added comment: Comment on mode of inheritance: Three unrelated cases have been reported with biallelic SPTAN1 variants (PMID: 31515523 & 34526651) . Neuropathy or pain was not part of the complex phenotypes that was seen in these cases.
Hereditary neuropathy or pain disorder v3.48 SPTAN1 Sarah Leigh Mode of inheritance for gene: SPTAN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset hereditary spastic paraplegia v4.18 SPTAN1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: Although there are three unrelated cases reported with biallelic SPTAN1 variants and hereditary spastic paraplegia, the age of onset of these cases were 33, 15 and 12 years (PMID:31515523; PMID:34526651). As the number of childhood-onset biallelic cases are not sufficient for green rating, the MOI should remain as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Childhood onset hereditary spastic paraplegia v4.18 SPTAN1 Achchuthan Shanmugasundram Mode of inheritance for gene: SPTAN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia with onset in adulthood v4.19 SPTAN1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: Although there are three unrelated cases reported with biallelic SPTAN1 variants and hereditary spastic paraplegia, they do not present with ataxia (PMID:31515523; PMID:34526651). Hence, the MOI should remain as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Hereditary ataxia with onset in adulthood v4.19 SPTAN1 Achchuthan Shanmugasundram Mode of inheritance for gene: SPTAN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - narrow panel v4.29 SPTAN1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: Although there are three unrelated cases reported with biallelic SPTAN1 variants and hereditary spastic paraplegia, they do not present with ataxia (PMID:31515523; PMID:34526651). Hence, the MOI should remain as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Ataxia and cerebellar anomalies - narrow panel v4.29 SPTAN1 Achchuthan Shanmugasundram Mode of inheritance for gene: SPTAN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ectodermal dysplasia v3.7 LRP6 Mafalda Gomes Publications for gene: LRP6 were set to
Ectodermal dysplasia v3.6 LRP6 Mafalda Gomes Deleted their comment
Ectodermal dysplasia v3.6 LRP6 Mafalda Gomes edited their review of gene: LRP6: Added comment: Massink et al. (2015) report the first association between LRP6 and oligodontia. LRP6 is a major component of the Wnt receptor complex in the canonical Wnt pathway. Other genes involved in this pathway, such as WNT10A, have been shown to be associated with oligodontia as well.
4 unrelated individuals with nonsyndromic oligodontia (12-20 missing teeth each) are reported: 3 carry heterozygous truncating variants in the LRP6 gene, and 1 carries a missense variant (p.Ala19Val) of a conserved residue located at the cleavage site of the protein's signal peptide. Functional studies showed that the missense variant results in altered glycosylation and improper subcellular localisation of the protein, resulting in abrogated activation of the Wnt pathway. Segregation studies confirmed presence of the variants in 6 additional affected family members across the 3 families with truncating variants. Incomplete penetrance was observed in the family of the individual with the missense variant, where the mother was found to be a carrier and is unaffected.
Lastly, an affected father and 2 daughters showed minor anatomical variation of the ear and underdevelopment of the thumb. No other anomalies described in the cohort.
Ockeloen et al. (2016) report 2 additional probands with oligodontia, one of which also had orofacial cleft, and perform a study among 67 patients with tooth agenesis, 1,073 patients with orofacial clefts, and 706 controls. They found significant enrichment of LRP6 rare variants in patients with tooth agenesis, but not in patients with nonsyndromic orofacial clefts. Five variants were identified in patients with tooth agenesis and shown to segregate in the 4 families (1 variant was de novo). Immunochemistry studies on embryonic mice showed that the gene is expressed in areas of bone formation, including the tooth follicle, suggesting a role in early tooth development.
Therefore, this gene should be promoted GREEN in this panel.; Changed rating: GREEN; Changed phenotypes to: Tooth agenesis, selective, 7, OMIM:616724
Ectodermal dysplasia v3.6 LRP6 Mafalda Gomes Phenotypes for gene: LRP6 were changed from to Tooth agenesis, selective, 7, OMIM:616724
Ectodermal dysplasia v3.5 LRP6 Mafalda Gomes Classified gene: LRP6 as Amber List (moderate evidence)
Ectodermal dysplasia v3.5 LRP6 Mafalda Gomes Gene: lrp6 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v3.4 LRP6 Mafalda Gomes Tag Q3_23_promote_green tag was added to gene: LRP6.
Ectodermal dysplasia v3.4 LRP6 Mafalda Gomes reviewed gene: LRP6: Rating: AMBER; Mode of pathogenicity: None; Publications: 26387593, 26963285; Phenotypes: Tooth agenesis, selective, 7; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ectodermal dysplasia v3.4 LRP6 Mafalda Gomes gene: LRP6 was added
gene: LRP6 was added to Ectodermal dysplasia. Sources: Literature
Mode of inheritance for gene: LRP6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Penetrance for gene: LRP6 were set to Incomplete
Intellectual disability v5.255 FAM111A Tracy Lester reviewed gene: FAM111A: Rating: RED; Mode of pathogenicity: None; Publications: 23684011, 37023242; Phenotypes: Skeletal dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v4.78 PANK2 Achchuthan Shanmugasundram Publications for gene: PANK2 were set to 11479594; 12510040; 25778941; 28863176
Mitochondrial disorders v4.78 PANK2 Achchuthan Shanmugasundram Publications for gene: PANK2 were set to 25778941; 11479594; 12510040; 28863176; 25778941
Possible mitochondrial disorder - nuclear genes v3.46 PANK2 Achchuthan Shanmugasundram Publications for gene: PANK2 were set to
Possible mitochondrial disorder - nuclear genes v3.45 PANK2 Achchuthan Shanmugasundram edited their review of gene: PANK2: Changed publications to: 11479594, 12510040, 25778941, 28863176
Possible mitochondrial disorder - nuclear genes v3.45 PANK2 Achchuthan Shanmugasundram Classified gene: PANK2 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.45 PANK2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for this gene to be promoted to green rating in the next major update.
Possible mitochondrial disorder - nuclear genes v3.45 PANK2 Achchuthan Shanmugasundram Gene: pank2 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.44 PANK2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PANK2.
Possible mitochondrial disorder - nuclear genes v3.44 PANK2 Achchuthan Shanmugasundram reviewed gene: PANK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25778941, 11479594, 12510040, 28863176, 25778941; Phenotypes: HARP syndrome, OMIM:607236, Neurodegeneration with brain iron accumulation 1, OMIM:234200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.77 PANK2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PANK2.
Mitochondrial disorders v4.77 PANK2 Achchuthan Shanmugasundram Deleted their comment
Mitochondrial disorders v4.77 PANK2 Achchuthan Shanmugasundram Classified gene: PANK2 as Amber List (moderate evidence)
Mitochondrial disorders v4.77 PANK2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PANK2 is a mitochondrial enzyme and there is sufficient evidence for promoting this gene to green rating at the next major update.
Mitochondrial disorders v4.77 PANK2 Achchuthan Shanmugasundram Gene: pank2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.77 PANK2 Achchuthan Shanmugasundram Classified gene: PANK2 as Amber List (moderate evidence)
Mitochondrial disorders v4.77 PANK2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PANK2 is a mitochondrial enzyme and there is sufficient evidence for promoting this gene to green rating at the next major update.
Mitochondrial disorders v4.77 PANK2 Achchuthan Shanmugasundram Gene: pank2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.76 PANK2 Achchuthan Shanmugasundram commented on gene: PANK2: This gene has been associated with relevant phenotypes in both OMIM (MIMs #607236 & #234200) and in Gene2Phenotype (HARP syndrome with 'definitive' rating in the eye panel).
Mitochondrial disorders v4.76 PANK2 Achchuthan Shanmugasundram Phenotypes for gene: PANK2 were changed from Neurodegeneration with brain iron accumulation 1, 234200HARP syndrome, 607236 to HARP syndrome, OMIM:607236; Neurodegeneration with brain iron accumulation 1, OMIM:234200
Mitochondrial disorders v4.75 PANK2 Achchuthan Shanmugasundram Publications for gene: PANK2 were set to 25778941; 11479594; 12510040; 28863176; 25778941
Mitochondrial disorders v4.75 PANK2 Achchuthan Shanmugasundram Publications for gene: PANK2 were set to
Mitochondrial disorders v4.74 PANK2 Achchuthan Shanmugasundram Mode of inheritance for gene: PANK2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.74 PANK2 Achchuthan Shanmugasundram Mode of inheritance for gene: PANK2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.73 PANK2 Achchuthan Shanmugasundram reviewed gene: PANK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: HARP syndrome, OMIM:607236, Neurodegeneration with brain iron accumulation 1, OMIM:234200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.255 CMIP Tord Jonson edited their review of gene: CMIP: Changed phenotypes to: HP:0012759 Neurodevelopmental abnormality, HP:0000717 Autism, HP:0007018 Attention deficit hyperactivity disorder, HP:0001250 Seizure, HP:0011471 Gastrostomy tube feeding in infancy
Intellectual disability v5.255 CMIP Tord Jonson changed review comment from: CMIP (MANE Select NM_198390) loss of function-variants (deletions) have been reported in two studies that describes patients with syndromic ASD and co-morbid gastrointestinal issues. See Van der Aa et al., 2012, Haploinsufficiency of CMIP in a girl with autism spectrum disorder and developmental delay due to a de novo deletion on chromosome 16q23.2 (PMID: 22689534); and Luo et al., 2017, CMIP haploinsufficiency in two patients with autism spectrum disorder and co-occurring gastrointestinal issues (PMID: 28504353). In addition, we have observed a local case with a de novo deletion encompassing only the genes CMIP and GAN in a patient with gastrostomy, intellectual disability, autism, ADHD and seizures.
Sources: Other; to: CMIP (MANE Select NM_198390) loss of function-variants (deletions) have been reported in two studies that describes patients with syndromic ASD and co-morbid gastrointestinal issues. See Van der Aa et al., 2012, Haploinsufficiency of CMIP in a girl with autism spectrum disorder and developmental delay due to a de novo deletion on chromosome 16q23.2 (PMID: 22689534); and Luo et al., 2017, CMIP haploinsufficiency in two patients with autism spectrum disorder and co-occurring gastrointestinal issues (PMID: 28504353). In addition, we have observed a local case with a de novo deletion encompassing only the genes CMIP and GAN in a patient with gastrostomy, intellectual disability, autism, ADHD and seizures.
Intellectual disability v5.255 CMIP Tord Jonson gene: CMIP was added
gene: CMIP was added to Intellectual disability - microarray and sequencing. Sources: Other
Mode of inheritance for gene: CMIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CMIP were set to PMID: 22689534; 28504353
Phenotypes for gene: CMIP were set to HP:0012759; HP:0000717; HP:0007018; HP:0001250; HP:0011471
Penetrance for gene: CMIP were set to unknown
Review for gene: CMIP was set to GREEN
gene: CMIP was marked as current diagnostic
Added comment: CMIP (MANE Select NM_198390) loss of function-variants (deletions) have been reported in two studies that describes patients with syndromic ASD and co-morbid gastrointestinal issues. See Van der Aa et al., 2012, Haploinsufficiency of CMIP in a girl with autism spectrum disorder and developmental delay due to a de novo deletion on chromosome 16q23.2 (PMID: 22689534); and Luo et al., 2017, CMIP haploinsufficiency in two patients with autism spectrum disorder and co-occurring gastrointestinal issues (PMID: 28504353). In addition, we have observed a local case with a de novo deletion encompassing only the genes CMIP and GAN in a patient with gastrostomy, intellectual disability, autism, ADHD and seizures.
Sources: Other
Hereditary neuropathy or pain disorder v3.47 SPTAN1 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: SPTAN1.
Hereditary neuropathy or pain disorder v3.47 SPTAN1 Sarah Leigh edited their review of gene: SPTAN1: Added comment: SPTAN1 variants have been associated with Developmental and epileptic encephalopathy 5 (OMIM:613477) and as definitive Gen2Phen gene for the same condition.; Changed rating: GREEN
Hereditary neuropathy or pain disorder v3.47 SPTAN1 Sarah Leigh Classified gene: SPTAN1 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.47 SPTAN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy or pain disorder v3.47 SPTAN1 Sarah Leigh Gene: sptan1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v4.18 SPTAN1 Sarah Leigh Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, OMIM:613477; Cerebellar ataxia, MONDO:0000437; Hereditary spastic paraplegia, MONDO:0019064 to Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277
Fetal anomalies v3.106 SPTAN1 Sarah Leigh Phenotypes for gene: SPTAN1 were changed from EPILEPTIC ENCEPHALOPATHY EARLY INFANTILE TYPE 5 to Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277
Adult onset hereditary spastic paraplegia v3.16 SPTAN1 Sarah Leigh Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, OMIM:613477; Cerebellar ataxia, MONDO:0000437; Hereditary spastic paraplegia, MONDO:0019064 to Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277
Childhood onset hereditary spastic paraplegia v4.17 SPTAN1 Sarah Leigh Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, OMIM:613477; Cerebellar ataxia, MONDO:0000437; Hereditary spastic paraplegia, MONDO:0019064 to Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277
Ataxia and cerebellar anomalies - narrow panel v4.28 SPTAN1 Sarah Leigh Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, OMIM:613477; Cerebellar ataxia, MONDO:0000437; Hereditary spastic paraplegia, MONDO:0019064 to Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277
Hereditary neuropathy or pain disorder v3.46 SPTAN1 Sarah Leigh Phenotypes for gene: SPTAN1 were changed from Hereditary motor neuropathy to Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277
Bleeding and platelet disorders v3.2 BLOC1S5 Hannah Knight reviewed gene: BLOC1S5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34685610, 34058075; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v3.8 RHOBTB2 Sarah Leigh edited their review of gene: RHOBTB2: Added comment: RHOBTB2 variant have been associated with Developmental and epileptic encephalopathy 64 (OMIM:618004) and as strong Gen2Phen gene for the same condition. PMID: 29276004 reports five RHOBTB2 variants in unrelated cases of OMIM:618004. The authors also present supportive functional studies.; Changed rating: GREEN; Changed publications to: 29276004
Paroxysmal central nervous system disorders v3.8 RHOBTB2 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: RHOBTB2.
Tag Q3_23_MOI tag was added to gene: RHOBTB2.
Paroxysmal central nervous system disorders v3.8 RHOBTB2 Sarah Leigh Phenotypes for gene: RHOBTB2 were changed from Developmental and epileptic encephalopathy 64 618004; Alternating hemiplegia to Developmental and epileptic encephalopathy 64, OMIM:618004; developmental and epileptic encephalopathy, 64, MONDO:0033373
Paroxysmal central nervous system disorders v3.7 RHOBTB2 Sarah Leigh Classified gene: RHOBTB2 as Amber List (moderate evidence)
Paroxysmal central nervous system disorders v3.7 RHOBTB2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Paroxysmal central nervous system disorders v3.7 RHOBTB2 Sarah Leigh Gene: rhobtb2 has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v3.6 ALPK1 Sarah Leigh changed review comment from: ALPK1 variants have been associated with ROSAH syndrome (OMIM:614979) and as strong Gen2Phen gene for the same condition. To date, 20 patients from 12 unrelated families carry NM_025144.4(ALPK1):c.710C>T (p.Thr237Met)(PMID: 30967659; 31939038; 35868845) and one case negative for this variant carried: ALPK1(NM_025144.4):c.761A>G (p.Tyr254Cys)(PMID: 35868845). These variants are in the ligand binding domain of ALPK1 and have a gain-of-function action, resulting in enhanced NF-κB activation in transfected cells and fibroblasts from patients with ROSAH syndrome (PMID: 35868845)..; to: ALPK1 variants have been associated with ROSAH syndrome (OMIM:614979) and as strong Gen2Phen gene for the same condition. To date, 20 patients from 12 unrelated families carry NM_025144.4(ALPK1):c.710C>T (p.Thr237Met)(PMID: 30967659; 31939038; 35868845) and one case negative for this variant carried: ALPK1(NM_025144.4):c.761A>G (p.Tyr254Cys)(PMID: 35868845). These variants are in the ligand binding domain of ALPK1 and have a gain-of-function action, resulting in enhanced NF-κB activation in transfected cells and fibroblasts from patients with ROSAH syndrome (PMID: 35868845).
Paroxysmal central nervous system disorders v3.6 ALPK1 Sarah Leigh Publications for gene: ALPK1 were set to 30967659; 31939038; 35868845
Optic neuropathy v4.11 ALPK1 Sarah Leigh reviewed gene: ALPK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Retinal disorders v4.24 ALPK1 Sarah Leigh reviewed gene: ALPK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paroxysmal central nervous system disorders v3.5 ALPK1 Sarah Leigh edited their review of gene: ALPK1: Added comment: ALPK1 variants have been associated with ROSAH syndrome (OMIM:614979) and as strong Gen2Phen gene for the same condition. To date, 20 patients from 12 unrelated families carry NM_025144.4(ALPK1):c.710C>T (p.Thr237Met)(PMID: 30967659; 31939038; 35868845) and one case negative for this variant carried: ALPK1(NM_025144.4):c.761A>G (p.Tyr254Cys)(PMID: 35868845). These variants are in the ligand binding domain of ALPK1 and have a gain-of-function action, resulting in enhanced NF-κB activation in transfected cells and fibroblasts from patients with ROSAH syndrome (PMID: 35868845)..; Changed rating: GREEN
Paroxysmal central nervous system disorders v3.5 ALPK1 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: ALPK1.
Tag Q3_23_MOI tag was added to gene: ALPK1.
Paroxysmal central nervous system disorders v3.5 ALPK1 Sarah Leigh Classified gene: ALPK1 as Amber List (moderate evidence)
Paroxysmal central nervous system disorders v3.5 ALPK1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Paroxysmal central nervous system disorders v3.5 ALPK1 Sarah Leigh Gene: alpk1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.24 ALPK1 Sarah Leigh Publications for gene: ALPK1 were set to 30967659; 31939038; 31053777; 34159509
Optic neuropathy v4.11 ALPK1 Sarah Leigh Publications for gene: ALPK1 were set to 30967659; 31053777; 31939038; 34159509
Primary immunodeficiency or monogenic inflammatory bowel disease v4.23 ALPK1 Sarah Leigh Publications for gene: ALPK1 were set to 35868845
Paroxysmal central nervous system disorders v3.4 ALPK1 Sarah Leigh Phenotypes for gene: ALPK1 were changed from ROSAH syndrome to ROSAH syndrome, OMIM:614979; optic nerve edema-splenomegaly syndrome, MONDO:0013999
Paroxysmal central nervous system disorders v3.3 ALPK1 Sarah Leigh Publications for gene: ALPK1 were set to 30967659; 31939038
Paroxysmal central nervous system disorders v3.2 ALPK1 Sarah Leigh Publications for gene: ALPK1 were set to PMID: 30967659
Intellectual disability v5.255 PABPC1 Sarah Leigh Tag Q3_23_phenotype tag was added to gene: PABPC1.
Early onset or syndromic epilepsy v4.85 PABPC1 Sarah Leigh edited their review of gene: PABPC1: Added comment: PABPC1 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35511136 reports four de novo PABPC1 variants in four unrelated cases with a phenotype of global DD, movement coordination disorders,
seizures, behavioral disorders and mild facial dysmorphisms. Intellectual disability ranged in the cases from profound (1/4), IQ: 61 (1/4) and IQ: 79 (2/4). Seizures were apparent in the all of the three cases where it was assessed.
Molecular modeling of the variants suggested that they would result in a reduced binding affinity to the messenger RNA metabolism-related protein - PAIP2. This predicted effect was seen in coimmunoprecipitation assays between variant PABPC1 and PAIP2 (PMID: 35511136). Further functional studies in PMID: 35511136, showed that the proliferation of neural progenitor cells in Pabpc1 knockdown mouse embryo brains were decreased, this effect was rescued by the wild-type Pabpc1, but not by the variants c.1691A>G (p.Glu564Gly) or c.1709T>C (p.Ile570Thr).
Other variants were identified in 3/4 cases in PMID: 35511136, two of these had a ACMG VUS classification (RBBP4: c.845A>G, p.(Asn282Ser), IGF2R: c.1850G>A p.Cys617Tyr), while the third variant was monoallelic, whereas bialleic variants in this gene are associated with disease (KDM5B: c.2265dupA, p.(Tyr755*))(PMID: 35511136, table 1).; Changed rating: GREEN
Intellectual disability v5.255 PABPC1 Sarah Leigh edited their review of gene: PABPC1: Added comment: PABPC1 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35511136 reports four de novo PABPC1 variants in four unrelated cases with a phenotype of global DD, movement coordination disorders,
seizures, behavioral disorders and mild facial dysmorphisms. Intellectual disability ranged in the cases from profound (1/4), IQ: 61 (1/4) and IQ: 79 (2/4). Seizures were apparent in the all of the three cases where it was assessed.
Molecular modeling of the variants suggested that they would result in a reduced binding affinity to the messenger RNA metabolism-related protein - PAIP2. This predicted effect was seen in coimmunoprecipitation assays between variant PABPC1 and PAIP2 (PMID: 35511136). Further functional studies in PMID: 35511136, showed that the proliferation of neural progenitor cells in Pabpc1 knockdown mouse embryo brains were decreased, this effect was rescued by the wild-type Pabpc1, but not by the variants c.1691A>G (p.Glu564Gly) or c.1709T>C (p.Ile570Thr).
Other variants were identified in 3/4 cases in PMID: 35511136, two of these had a ACMG VUS classification (RBBP4: c.845A>G, p.(Asn282Ser), IGF2R: c.1850G>A p.Cys617Tyr), while the third variant was monoallelic, whereas bialleic variants in this gene are associated with disease (KDM5B: c.2265dupA, p.(Tyr755*))(PMID: 35511136, table 1).; Changed rating: GREEN
Intellectual disability v5.255 PABPC1 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: PABPC1.
Tag Q3_23_MOI tag was added to gene: PABPC1.
Early onset or syndromic epilepsy v4.85 PABPC1 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: PABPC1.
Tag Q3_23_MOI tag was added to gene: PABPC1.
Intellectual disability v5.255 PABPC1 Sarah Leigh Classified gene: PABPC1 as Amber List (moderate evidence)
Intellectual disability v5.255 PABPC1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v5.255 PABPC1 Sarah Leigh Gene: pabpc1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.85 PABPC1 Sarah Leigh Classified gene: PABPC1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.85 PABPC1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v4.85 PABPC1 Sarah Leigh Gene: pabpc1 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.44 OXCT1 Achchuthan Shanmugasundram Classified gene: OXCT1 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.44 OXCT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available, this gene can be promoted to green rating in this panel in the next major update.
Possible mitochondrial disorder - nuclear genes v3.44 OXCT1 Achchuthan Shanmugasundram Gene: oxct1 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.43 OXCT1 Achchuthan Shanmugasundram Publications for gene: OXCT1 were set to
Possible mitochondrial disorder - nuclear genes v3.42 OXCT1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: OXCT1.
Possible mitochondrial disorder - nuclear genes v3.42 OXCT1 Achchuthan Shanmugasundram reviewed gene: OXCT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8751852, 10964512, 11757586, 23420214, 25778941; Phenotypes: Succinyl CoA:3-oxoacid CoA transferase deficiency, OMIM:24505; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.73 OXCT1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: OXCT1.
Mitochondrial disorders v4.73 OXCT1 Achchuthan Shanmugasundram Classified gene: OXCT1 as Amber List (moderate evidence)
Mitochondrial disorders v4.73 OXCT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence available (at least three unrelated cases and functional evidence) in support of the association of this gene to Succinyl CoA:3-oxoacid CoA transferase deficiency (a mitochondrial enzyme).

In addition, this gene has been associated with this phenotype in both OMIM (MIM #245050) and Gene2Phenotype ('definitive' rating in the DD panel.

This gene can therefore be promoted to green rating in the next GMS update.
Mitochondrial disorders v4.73 OXCT1 Achchuthan Shanmugasundram Gene: oxct1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.72 OXCT1 Achchuthan Shanmugasundram Publications for gene: OXCT1 were set to
Mitochondrial disorders v4.71 OXCT1 Achchuthan Shanmugasundram reviewed gene: OXCT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8751852, 10964512, 11757586, 23420214, 25778941; Phenotypes: Succinyl CoA:3-oxoacid CoA transferase deficiency, OMIM:245050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting v4.93 TBL1XR1 Achchuthan Shanmugasundram Classified gene: TBL1XR1 as Amber List (moderate evidence)
Clefting v4.93 TBL1XR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although three patients are reported with clefting in total, this represents a small fraction of total cases with monoallelic TBL1XR1 variants. Hence, this gene should be rated amber.
Clefting v4.93 TBL1XR1 Achchuthan Shanmugasundram Gene: tbl1xr1 has been classified as Amber List (Moderate Evidence).
Clefting v4.92 TBL1XR1 Achchuthan Shanmugasundram gene: TBL1XR1 was added
gene: TBL1XR1 was added to Clefting. Sources: Literature
Mode of inheritance for gene: TBL1XR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBL1XR1 were set to 28687524; 37010288
Phenotypes for gene: TBL1XR1 were set to Pierpont syndrome, OMIM:602342
Review for gene: TBL1XR1 was set to AMBER
Added comment: PMID:28687524 - A seven year-old boy reported with severe developmental delays, hypotonia and dysmorphic features and identified with a de novo heterozygous variant (p.Tyr446Cys) in TBL1XR1 gene had submucous cleft palate.

DECIPHER database - One of 34 patients with heterozygous sequence variants in TBL1XR1 gene in DECIPHER database had orofacial cleft and another patient had unilateral cleft lip and palate.
Sources: Literature
Clefting v4.91 CDK13 Achchuthan Shanmugasundram changed review comment from: PMID:29222009 - One of three patients reported with de novo heterozygous CDK13 variants had submucosal cleft palate.

DECIPHER database - Only one of 42 patients reported with heterozygous sequence variants in CDK13 gene had orofacial cleft as one of the phenotypes.
Sources: Literature; to: Clefting was reported only in a minor proportion of patients with monoallelic CDK13 variants.

PMID:29222009 - One of three patients reported with de novo heterozygous CDK13 variants had submucosal cleft palate.

DECIPHER database - Only one of 42 patients reported with heterozygous sequence variants in CDK13 gene had orofacial cleft as one of the phenotypes.
Sources: Literature
Clefting v4.91 CDK13 Achchuthan Shanmugasundram changed review comment from: PMID:29222009 - One of three patients reported with de novo heterozygous CDK13 variants had submucosal cleft palate.

DECIPHER database - Only one of 42 patients reported with heterozygous sequence variants in CDK13 gene had orofacial cleft as one of the phenotypes.
Sources: Literature; to: PMID:29222009 - One of three patients reported with de novo heterozygous CDK13 variants had submucosal cleft palate.

DECIPHER database - Only one of 42 patients reported with heterozygous sequence variants in CDK13 gene had orofacial cleft as one of the phenotypes.
Sources: Literature
Clefting v4.91 CDK13 Achchuthan Shanmugasundram gene: CDK13 was added
gene: CDK13 was added to Clefting. Sources: Literature
Mode of inheritance for gene: CDK13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDK13 were set to 29222009; 37010288
Review for gene: CDK13 was set to RED
Added comment: PMID:29222009 - One of three patients reported with de novo heterozygous CDK13 variants had submucosal cleft palate.

DECIPHER database - Only one of 42 patients reported with heterozygous sequence variants in CDK13 gene had orofacial cleft as one of the phenotypes.
Sources: Literature
Clefting v4.90 NEB Achchuthan Shanmugasundram changed review comment from: PMID:12207937 - A 9 month-old boy from one of five families affected by nemaline myopathy and reported with NEB variants had cleft palate. This patient was homozygous for 1-bp deletion in exon 184, which was also found in the mother, whereas no DNA was available from father.

PMID:21798101 - Two siblings were reported with severe arthrogryposis multiplex congenital and were identified with compound heterozygous variants in NEB gene (c.1152 + 1G > T & c.11318_11319del), of which one patient had cleft palate.

PMID:33376055 - A male foetus of consanguineous parents with a severe congenital syndrome characterized by arthrogryposis detected at 13 weeks of gestation had cleft palate and was identified with homozygous splice-site NEB variant (c.19,102-1G>T).

DECIPHER databse - Of 10 patients with biallelic (compound heterozygous or homozygous) sequence variants in NEB gene reported in DECIPHER database, one patient with compound heterozygous NEB variants had bifid uvula.
Sources: Literature; to: PMID:12207937 - A 9 month-old boy from one of five families affected by nemaline myopathy and reported with NEB variants had cleft palate. This patient was homozygous for 1-bp deletion in exon 184, which was also found in the mother, whereas no DNA was available from father.

PMID:21798101 - Two siblings were reported with severe arthrogryposis multiplex congenital and were identified with compound heterozygous variants in NEB gene (c.1152 + 1G > T & c.11318_11319del), of which one patient had cleft palate.

PMID:33376055 - A male foetus of consanguineous parents with a severe congenital syndrome characterized by arthrogryposis detected at 13 weeks of gestation had cleft palate and was identified with homozygous splice-site NEB variant (c.19,102-1G>T).

DECIPHER databse - Of 10 patients with biallelic (compound heterozygous or homozygous) sequence variants in NEB gene reported in DECIPHER database, one patient with compound heterozygous NEB variants had bifid uvula.

Cleft palate has been associated as one of the clinical presentations of Arthrogryposis multiplex congenita 6 (MIM #619334) in OMIM.
Sources: Literature
Clefting v4.90 NEB Achchuthan Shanmugasundram Publications for gene: NEB were set to 12207937; 21798101; 33376055
Clefting v4.89 NEB Achchuthan Shanmugasundram edited their review of gene: NEB: Changed publications to: 12207937, 21798101, 33376055, 37010288
Clefting v4.89 ECEL1 Achchuthan Shanmugasundram Classified gene: ECEL1 as Amber List (moderate evidence)
Clefting v4.89 ECEL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are more than three cases reported with clefting, it is only present in a small subsection (<10%) of patients with ECEL1 biallelic variants. Hence, this gene should be rated amber.
Clefting v4.89 ECEL1 Achchuthan Shanmugasundram Gene: ecel1 has been classified as Amber List (Moderate Evidence).
Clefting v4.88 NEB Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Although there are three unrelated cases reported with cleft palate in literature and a case reported with bifid uvula in the DECIPHER project, clefting has not been consistently reported as a phenotype in patients with biallelic NEB variants and is not fully penetrant in some families .; to: Comment on list classification: Although there are three unrelated cases reported with cleft palate in literature and a case reported with bifid uvula in the DECIPHER project, clefting has not been consistently reported as a phenotype in patients with biallelic NEB variants and is not fully penetrant in at least one family with clefting.
Clefting v4.88 NEB Achchuthan Shanmugasundram Classified gene: NEB as Amber List (moderate evidence)
Clefting v4.88 NEB Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are three unrelated cases reported with cleft palate in literature and a case reported with bifid uvula in the DECIPHER project, clefting has not been consistently reported as a phenotype in patients with biallelic NEB variants and is not fully penetrant in some families .
Clefting v4.88 NEB Achchuthan Shanmugasundram Gene: neb has been classified as Amber List (Moderate Evidence).
Clefting v4.87 NEB Achchuthan Shanmugasundram gene: NEB was added
gene: NEB was added to Clefting. Sources: Literature
Mode of inheritance for gene: NEB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEB were set to 12207937; 21798101; 33376055
Phenotypes for gene: NEB were set to Arthrogryposis multiplex congenita 6, OMIM:619334
Review for gene: NEB was set to AMBER
Added comment: PMID:12207937 - A 9 month-old boy from one of five families affected by nemaline myopathy and reported with NEB variants had cleft palate. This patient was homozygous for 1-bp deletion in exon 184, which was also found in the mother, whereas no DNA was available from father.

PMID:21798101 - Two siblings were reported with severe arthrogryposis multiplex congenital and were identified with compound heterozygous variants in NEB gene (c.1152 + 1G > T & c.11318_11319del), of which one patient had cleft palate.

PMID:33376055 - A male foetus of consanguineous parents with a severe congenital syndrome characterized by arthrogryposis detected at 13 weeks of gestation had cleft palate and was identified with homozygous splice-site NEB variant (c.19,102-1G>T).

DECIPHER databse - Of 10 patients with biallelic (compound heterozygous or homozygous) sequence variants in NEB gene reported in DECIPHER database, one patient with compound heterozygous NEB variants had bifid uvula.
Sources: Literature
Clefting v4.86 ECEL1 Achchuthan Shanmugasundram changed review comment from: PMID:3013119 - Seven individuals from four unrelated families were reported with a wide phenotypic spectrum including severe congenital contractural syndromes and distal arthrogryposis type 5D and were identified with biallelic variants in ECEL1 gene. Of these two individuals from two different families presented with cleft palate. However, literature review in this publication showed only three patients from a total of 34 had cleft palate (9%).

DECIPHER database - The only patient reported in DECIPHER with compound heterozygous sequence variants in ECEL1 gene had cleft soft palate.

This gene was associated with distal arthrogryposis in both OMIM (MIM #615065) and Gene2Phenotype ('definitive' rating in the DD panel). OMIM recorded cleft palate as one of the clinical manifestations affecting some patients with this disorder.
Sources: Literature; to: PMID:3013119 - Seven individuals from four unrelated families were reported with a wide phenotypic spectrum including severe congenital contractural syndromes and distal arthrogryposis type 5D and were identified with biallelic variants in ECEL1 gene. Of these two individuals from two different families presented with cleft palate. However, literature review in this publication showed that only three patients from a total of 34 patients with biallelic ECEL1 variants had cleft palate (9%).

DECIPHER database - The only patient reported in DECIPHER with compound heterozygous sequence variants in ECEL1 gene had cleft soft palate.

This gene was associated with distal arthrogryposis in both OMIM (MIM #615065) and Gene2Phenotype ('definitive' rating in the DD panel). OMIM recorded cleft palate as one of the clinical manifestations affecting some patients with this disorder.
Sources: Literature
Clefting v4.86 ECEL1 Achchuthan Shanmugasundram gene: ECEL1 was added
gene: ECEL1 was added to Clefting. Sources: Literature
Mode of inheritance for gene: ECEL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ECEL1 were set to 30131190; 37010288
Phenotypes for gene: ECEL1 were set to Arthrogryposis, distal, type 5D, OMIM:615065
Review for gene: ECEL1 was set to AMBER
Added comment: PMID:3013119 - Seven individuals from four unrelated families were reported with a wide phenotypic spectrum including severe congenital contractural syndromes and distal arthrogryposis type 5D and were identified with biallelic variants in ECEL1 gene. Of these two individuals from two different families presented with cleft palate. However, literature review in this publication showed only three patients from a total of 34 had cleft palate (9%).

DECIPHER database - The only patient reported in DECIPHER with compound heterozygous sequence variants in ECEL1 gene had cleft soft palate.

This gene was associated with distal arthrogryposis in both OMIM (MIM #615065) and Gene2Phenotype ('definitive' rating in the DD panel). OMIM recorded cleft palate as one of the clinical manifestations affecting some patients with this disorder.
Sources: Literature
Short stature - SHOX deficiency v0.1 SHOX Achchuthan Shanmugasundram Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Barth syndrome v0.1 TAZ Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: TAZ.
Gaucher disease v0.1 GBA Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: GBA.
Clefting v4.85 CDKL5 Achchuthan Shanmugasundram changed review comment from: Sources: Literature; to: Of 16 patients with sequence variants in CDKL5 in the DECIPHER database (https://www.deciphergenomics.org/), one of them had median cleft palate and another one had orofacial cleft.
Sources: Literature
Clefting v4.85 CDKL5 Achchuthan Shanmugasundram gene: CDKL5 was added
gene: CDKL5 was added to Clefting. Sources: Literature
Mode of inheritance for gene: CDKL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDKL5 were set to 37010288
Review for gene: CDKL5 was set to RED
Added comment: Sources: Literature
Clefting v4.83 CSNK2A1 Achchuthan Shanmugasundram gene: CSNK2A1 was added
gene: CSNK2A1 was added to Clefting. Sources: Literature
Mode of inheritance for gene: CSNK2A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CSNK2A1 were set to 37010288
Review for gene: CSNK2A1 was set to RED
Added comment: Of 21 patients with sequence variants in CSNK2A1 gene in the DECIPHER database (https://www.deciphergenomics.org/), two of them had cleft palate.
Sources: Literature
Clefting v4.82 SOX5 Achchuthan Shanmugasundram gene: SOX5 was added
gene: SOX5 was added to Clefting. Sources: Literature
Mode of inheritance for gene: SOX5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOX5 were set to 37010288
Review for gene: SOX5 was set to RED
Added comment: Of 19 patients with sequence variants in SOX5 gene in the DECIPHER database (https://www.deciphergenomics.org/), one had cleft palate and another one had bifid uvula/ submucous cleft hard palate.
Sources: Literature
Clefting v4.81 WDR26 Achchuthan Shanmugasundram gene: WDR26 was added
gene: WDR26 was added to Clefting. Sources: Literature
Mode of inheritance for gene: WDR26 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR26 were set to 37010288
Review for gene: WDR26 was set to RED
Added comment: Of 15 patients with sequence variants in WDR26 in the DECIPHER database (https://www.deciphergenomics.org/), two of them had (median) cleft palate.
Sources: Literature
Mitochondrial disorders v4.71 MRPS23 Achchuthan Shanmugasundram reviewed gene: MRPS23: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Distal myopathies v3.12 GIPC1 Sarah Leigh Classified gene: GIPC1 as Red List (low evidence)
Distal myopathies v3.12 GIPC1 Sarah Leigh Added comment: Comment on list classification: This gene will remain red as it is only the GIPC1_GGC expansion that has been associated with disease.
Distal myopathies v3.12 GIPC1 Sarah Leigh Gene: gipc1 has been classified as Red List (Low Evidence).
Distal myopathies v3.11 GIPC1 Sarah Leigh reviewed gene: GIPC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Distal myopathies v3.11 GIPC1 Sarah Leigh Phenotypes for gene: GIPC1 were changed from Oculopharyngodistal myopathy 2, OMIM:618940 to Oculopharyngodistal myopathy 2, OMIM:618940; oculopharyngodistal myopathy 2, MONDO:0030134
Distal myopathies v3.10 GIPC1 Sarah Leigh Tag STR tag was added to gene: GIPC1.
Distal myopathies v3.10 GIPC1 Sarah Leigh Classified gene: GIPC1 as Red List (low evidence)
Distal myopathies v3.10 GIPC1 Sarah Leigh Gene: gipc1 has been classified as Red List (Low Evidence).
Distal myopathies v3.9 GIPC1 Sarah Leigh Classified gene: GIPC1 as Amber List (moderate evidence)
Distal myopathies v3.9 GIPC1 Sarah Leigh Gene: gipc1 has been classified as Amber List (Moderate Evidence).
Distal myopathies v3.8 SMPX Sarah Leigh Tag Q3_23_promote_green tag was added to gene: SMPX.
Tag Q3_23_MOI tag was added to gene: SMPX.
Distal myopathies v3.8 SMPX Sarah Leigh edited their review of gene: SMPX: Added comment: Hemizygous variants in SMPX have been associated with Myopathy, distal, 7, adult-onset, X-linked (OMIM:301075), but not been associated with phenotype in Gen2Phen. PMID: 33974137 reports four SMPX variants in seven families without shared haplotypes. In vitro studies suggested a gain-of-function action of these variants, resulting a protein that was less soluble compared to wildtype, which in some cases had a tendency to aggregate.; Changed rating: GREEN
Childhood onset dystonia, chorea or related movement disorder v3.38 L2HGDH Achchuthan Shanmugasundram changed review comment from: PMID:15824270 - A 15 year-old boy with L-2-hydroxyglutaric aciduria was reported with early infantile-onset progressive psychomotor regression, mild choreodystonia affecting the distal part of the upper limbs, pyramidal signs, and epilepsy.

PMID:18780161 - Of seven patients from three unrelated Tunisian families with L-2-hydroxyglutaric aciduria and with homozygous variants in L2HGDH gene, three patients from two different families had dystonia.

PMID:24753671 - Two siblings were reported with dystonia diagnosed by classical neuroimaging findings with elevated urinary 2 hydroxyglutaric acid.; to: PMID:15824270 - A 15 year-old boy with L-2-hydroxyglutaric aciduria was reported with early infantile-onset progressive psychomotor regression, mild choreodystonia affecting the distal part of the upper limbs, pyramidal signs, and epilepsy.

PMID:18780161 - Of seven patients from three unrelated Tunisian families with L-2-hydroxyglutaric aciduria and with homozygous variants in L2HGDH gene, three patients from two different families had dystonia. The age of onset of the disorder in these patients is around six years.

PMID:24753671 - Two siblings (13 and 16 years of age with disease onset at 10 years of age) were reported with dystonia diagnosed by classical neuroimaging findings with elevated urinary 2 hydroxyglutaric acid.
Childhood onset dystonia, chorea or related movement disorder v3.38 SYT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are four unrelated cases with childhood-onset dystonia as a feature of Baker-Gordon syndrome. Hence, this gene should be promoted to green rating at the next major update.; to: Comment on list classification: As reviewed by Zornitza Stark, there are four unrelated children with dystonia as a feature of Baker-Gordon syndrome. Hence, this gene should be promoted to green rating at the next major update.
Childhood onset dystonia, chorea or related movement disorder v3.38 SYT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are four unrelated cases with dystonia as a feature of Baker-Gordon syndrome. Hence, this gene should be promoted to green rating at the next major update.; to: Comment on list classification: As reviewed by Zornitza Stark, there are four unrelated cases with childhood-onset dystonia as a feature of Baker-Gordon syndrome. Hence, this gene should be promoted to green rating at the next major update.
Distal myopathies v3.8 SMPX Sarah Leigh Phenotypes for gene: SMPX were changed from Distal myopathy to Myopathy, distal, 7, adult-onset, X-linked, OMIM:301075; myopathy, distal, 7, adult-onset, X-linked, MONDO:0024771
Distal myopathies v3.7 SMPX Sarah Leigh Publications for gene: SMPX were set to PMID: 33974137
Distal myopathies v3.6 SMPX Sarah Leigh Classified gene: SMPX as Amber List (moderate evidence)
Distal myopathies v3.6 SMPX Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Distal myopathies v3.6 SMPX Sarah Leigh Gene: smpx has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v4.15 SLC12A3 Sarah Leigh Phenotypes for gene: SLC12A3 were changed from Hypokalaemic alkalosis with hypomagnesaemia & hypocalciuria; Gitelman syndrome, 263800 to Gitelman syndrome, OMIM: 263800; Gitelman syndrome, MONDO:0009904
Likely inborn error of metabolism v4.46 SLC12A3 Sarah Leigh Phenotypes for gene: SLC12A3 were changed from Gitelman syndrome (Disorder of magnesium metabolism); Renal tubular acidosis to Gitelman syndrome, OMIM: 263800; Gitelman syndrome, MONDO:0009904
Childhood onset dystonia, chorea or related movement disorder v3.38 SLC12A3 Sarah Leigh Phenotypes for gene: SLC12A3 were changed from to Gitelman syndrome, OMIM: 263800; Gitelman syndrome, MONDO:0009904
Undiagnosed metabolic disorders v1.598 SLC12A3 Sarah Leigh Phenotypes for gene: SLC12A3 were changed from Gitelman syndrome (Disorder of magnesium metabolism); Renal tubular acidosis to Gitelman syndrome, OMIM: 263800; Gitelman syndrome, MONDO:0009904
Ductal plate malformation v1.27 SLC12A3 Sarah Leigh Phenotypes for gene: SLC12A3 were changed from Gitelman syndrome (263800) to Gitelman syndrome, OMIM: 263800; Gitelman syndrome, MONDO:0009904
Renal tubulopathies v4.14 SLC12A3 Sarah Leigh Tag monogenic-polygenic was removed from gene: SLC12A3.
Tag monogenic - polygenic tag was added to gene: SLC12A3.
Childhood onset dystonia, chorea or related movement disorder v3.37 SLC12A3 Sarah Leigh Tag monogenic-polygenic was removed from gene: SLC12A3.
Tag monogenic - polygenic tag was added to gene: SLC12A3.
Likely inborn error of metabolism v4.45 SLC12A3 Sarah Leigh Tag monogenic-polygenic was removed from gene: SLC12A3.
Tag monogenic - polygenic tag was added to gene: SLC12A3.
Ductal plate malformation v1.26 SLC12A3 Sarah Leigh Tag monogenic-polygenic was removed from gene: SLC12A3.
Tag monogenic - polygenic tag was added to gene: SLC12A3.
Renal tubulopathies v4.14 SLC12A3 Sarah Leigh Publications for gene: SLC12A3 were set to
Renal tubulopathies v4.13 SLC12A3 Sarah Leigh Tag monogenic-polygenic tag was added to gene: SLC12A3.
Childhood onset dystonia, chorea or related movement disorder v3.37 SLC12A3 Sarah Leigh Tag monogenic-polygenic tag was added to gene: SLC12A3.
Childhood onset dystonia, chorea or related movement disorder v3.37 SLC12A3 Sarah Leigh Publications for gene: SLC12A3 were set to
Likely inborn error of metabolism v4.45 SLC12A3 Sarah Leigh Publications for gene: SLC12A3 were set to 27604308
Likely inborn error of metabolism v4.44 SLC12A3 Sarah Leigh Tag monogenic-polygenic tag was added to gene: SLC12A3.
Undiagnosed metabolic disorders v1.597 SLC12A3 Sarah Leigh Publications for gene: SLC12A3 were set to 27604308
Ductal plate malformation v1.26 SLC12A3 Sarah Leigh Publications for gene: SLC12A3 were set to
Renal tubulopathies v4.13 SLC12A3 Sarah Leigh commented on gene: SLC12A3
Childhood onset dystonia, chorea or related movement disorder v3.36 SLC12A3 Sarah Leigh commented on gene: SLC12A3
Likely inborn error of metabolism v4.44 SLC12A3 Sarah Leigh commented on gene: SLC12A3: Heterozygous digenic SLC12A3 and CLCNKB variants have been associated with a variant of Gitelman syndrome (PMID: 26770037;30999883). However, the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Undiagnosed metabolic disorders v1.596 SLC12A3 Sarah Leigh commented on gene: SLC12A3: Heterozygous digenic SLC12A3 and CLCNKB variants have been associated with a variant of Gitelman syndrome (PMID: 26770037;30999883). However, the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Ductal plate malformation v1.25 SLC12A3 Sarah Leigh commented on gene: SLC12A3
Undiagnosed metabolic disorders v1.596 SLC12A3 Sarah Leigh Tag monogenic - polygenic tag was added to gene: SLC12A3.
Neonatal diabetes - small panel v0.2 Achchuthan Shanmugasundram List of related panels changed from R143 to R143; Neonatal diabetes
Ductal plate malformation v1.25 SLC12A3 Sarah Leigh Tag monogenic-polygenic tag was added to gene: SLC12A3.
Mucopolysaccharidosis type IH or S v0.3 Achchuthan Shanmugasundram List of related panels changed from R277 to R277; Mucopolysaccharidosis type IH/S
Mucolipidosis II and III Alpha or Beta v0.3 Achchuthan Shanmugasundram List of related panels changed from R289 to R289; Mucolipidosis II and III Alpha/Beta
Renal tubulopathies v4.13 SLC12A1 Sarah Leigh commented on gene: SLC12A1
Fetal anomalies v3.105 SLC12A1 Sarah Leigh commented on gene: SLC12A1
Nephrocalcinosis or nephrolithiasis v4.9 SLC12A1 Sarah Leigh commented on gene: SLC12A1
Renal tubulopathies v4.13 SLC12A1 Sarah Leigh Publications for gene: SLC12A1 were set to 8640224; 30999883; 32506365; 26770037; 27103762; 8640224; 9355073; 28095294; 32506365
Monogenic nephrogenic diabetes insipidus v1.11 SLC12A1 Sarah Leigh commented on gene: SLC12A1
Renal tubulopathies v4.12 SLC12A1 Sarah Leigh Tag monogenic-polygenic tag was added to gene: SLC12A1.
Fetal anomalies v3.105 SLC12A1 Sarah Leigh Tag monogenic-polygenic tag was added to gene: SLC12A1.
Nephrocalcinosis or nephrolithiasis v4.9 SLC12A1 Sarah Leigh Tag monogenic-polygenic tag was added to gene: SLC12A1.
Monogenic nephrogenic diabetes insipidus v1.11 SLC12A1 Sarah Leigh Tag monogenic-polygenic tag was added to gene: SLC12A1.
Renal tubulopathies v4.12 SLC12A1 Sarah Leigh Phenotypes for gene: SLC12A1 were changed from Type 1 Bartter syndrome: infantile onset, pregnancy noted for polyhydramnios. Hyperprostagladinuria. Hypokalaemia and metabolic alkalosis +/- nephrocalcinosis; Bartter syndrome, type 1, 601678 to Bartter syndrome, type 1, OMIM:601678; Bartter disease type 1, MONDO:0100344
Fetal anomalies v3.105 SLC12A1 Sarah Leigh Phenotypes for gene: SLC12A1 were changed from Bartter syndrome, type 1 601678 to Bartter syndrome, type 1, OMIM:601678; Bartter disease type 1, MONDO:0100344
Nephrocalcinosis or nephrolithiasis v4.9 SLC12A1 Sarah Leigh Phenotypes for gene: SLC12A1 were changed from Type 1 Bartter syndrome: infantile onset, pregnancy noted for polyhydramnios; Hyperprostagladinuria; Hypokalaemia and metabolic alkalosis +/- nephrocalcinosis; Antenatal Bartter Syndrome; Bartter syndrome, type 1, 601678 to Bartter syndrome, type 1, OMIM:601678; Bartter disease type 1, MONDO:0100344
Monogenic nephrogenic diabetes insipidus v1.11 SLC12A1 Sarah Leigh Phenotypes for gene: SLC12A1 were changed from hyperparathyroidism, hypercalcemia, nephrogenic diabetes insipidus, and nephrocalcinosis; associated with Barter syndrome and secondary inherited NDI only to Bartter syndrome, type 1, OMIM:601678; Bartter disease type 1, MONDO:0100344
Renal tubulopathies v4.11 SLC12A1 Sarah Leigh Publications for gene: SLC12A1 were set to 8640224; 30999883; 32506365; 26770037; 27103762
Fetal anomalies v3.104 SLC12A1 Sarah Leigh Publications for gene: SLC12A1 were set to
Nephrocalcinosis or nephrolithiasis v4.8 SLC12A1 Sarah Leigh Publications for gene: SLC12A1 were set to PMID: 21631963; 21189980; 20219833; 19513753; 19096086; 18830715; 17998760; 16807401
Monogenic nephrogenic diabetes insipidus v1.10 SLC12A1 Sarah Leigh Publications for gene: SLC12A1 were set to 28095294; 32506365
Monogenic nephrogenic diabetes insipidus v1.9 SLC12A1 Sarah Leigh Publications for gene: SLC12A1 were set to 28095294
Renal tubulopathies v4.10 CLCNKA Sarah Leigh Classified gene: CLCNKA as Red List (low evidence)
Renal tubulopathies v4.10 CLCNKA Sarah Leigh Gene: clcnka has been classified as Red List (Low Evidence).
Renal tubulopathies v4.9 CLCNKA Sarah Leigh Classified gene: CLCNKA as Red List (low evidence)
Renal tubulopathies v4.9 CLCNKA Sarah Leigh Added comment: Comment on list classification: The rating of this gene is being changed to Red from Amber, to reflect that GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Renal tubulopathies v4.9 CLCNKA Sarah Leigh Gene: clcnka has been classified as Red List (Low Evidence).
Intellectual disability v5.254 CLCNKA Sarah Leigh Phenotypes for gene: CLCNKA were changed from Bartter syndrome, type 4b, digenic, 613090; Infantile Bartter syndrome with sensorineural deafness, intellectual disability to Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 4B, MONDO:0000909
Renal tubulopathies v4.8 CLCNKA Sarah Leigh Phenotypes for gene: CLCNKA were changed from Bartter syndrome, type 4b, digenic, OMIM:613090 to Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 4B, MONDO:0000909
DDG2P v3.10 CLCNKA Sarah Leigh Phenotypes for gene: CLCNKA were changed from BARTTER SYNDROME TYPE 4B 613090 to Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 4B, MONDO:0000909
Nephrocalcinosis or nephrolithiasis v4.7 CLCNKA Sarah Leigh Phenotypes for gene: CLCNKA were changed from Bartter syndrome, type 4b, digenic, 613090 to Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 4B, MONDO:0000909
Intellectual disability v5.253 CLCNKA Sarah Leigh Publications for gene: CLCNKA were set to
Intellectual disability v5.253 CLCNKA Sarah Leigh Added comment: Comment on mode of inheritance: Digenic CLCNKA & CLCNKB variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090)(PMID: 15044642;18310267;32488762). The current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Intellectual disability v5.253 CLCNKA Sarah Leigh Mode of inheritance for gene: CLCNKA was changed from to Other
Nephrocalcinosis or nephrolithiasis v4.6 CLCNKA Sarah Leigh changed review comment from: Comment on mode of inheritance: Digenic CLCNKA & CLCNKB variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090)(PMID: 15044642;18310267). The current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.; to: Comment on mode of inheritance: Digenic CLCNKA & CLCNKB variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090)(PMID: 15044642;18310267;32488762). The current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
DDG2P v3.9 CLCNKA Sarah Leigh changed review comment from: Comment on mode of inheritance: Digenic CLCNKA & CLCNKB variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090)(PMID: 15044642;18310267). The current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.; to: Comment on mode of inheritance: Digenic CLCNKA & CLCNKB variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090)(PMID: 15044642;18310267;32488762). The current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Renal tubulopathies v4.7 CLCNKA Sarah Leigh Added comment: Comment on mode of inheritance: Digenic CLCNKA & CLCNKB variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090)(PMID: 15044642;18310267;32488762). The current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Renal tubulopathies v4.7 CLCNKA Sarah Leigh Mode of inheritance for gene: CLCNKA was changed from BIALLELIC, autosomal or pseudoautosomal to Other
Renal tubulopathies v4.6 CLCNKA Sarah Leigh Tag polygenic tag was added to gene: CLCNKA.
Renal tubulopathies v4.6 CLCNKA Sarah Leigh Publications for gene: CLCNKA were set to 18310267; 32488762
DDG2P v3.9 CLCNKA Sarah Leigh Publications for gene: CLCNKA were set to
Nephrocalcinosis or nephrolithiasis v4.6 CLCNKA Sarah Leigh Publications for gene: CLCNKA were set to 15044642; 18310267
DDG2P v3.8 CLCNKA Sarah Leigh Tag polygenic tag was added to gene: CLCNKA.
DDG2P v3.8 CLCNKA Sarah Leigh Added comment: Comment on mode of inheritance: Digenic CLCNKA & CLCNKB variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090)(PMID: 15044642;18310267). The current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
DDG2P v3.8 CLCNKA Sarah Leigh Mode of inheritance for gene: CLCNKA was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v4.5 CLCNKA Sarah Leigh Added comment: Comment on mode of inheritance: Digenic CLCNKA & CLCNKB variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090)(PMID: 15044642;18310267). The current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Nephrocalcinosis or nephrolithiasis v4.5 CLCNKA Sarah Leigh Mode of inheritance for gene: CLCNKA was changed from BIALLELIC, autosomal or pseudoautosomal to Other
Nephrocalcinosis or nephrolithiasis v4.4 CLCNKA Sarah Leigh Publications for gene: CLCNKA were set to
Nephrocalcinosis or nephrolithiasis v4.3 CLCNKA Sarah Leigh Tag polygenic tag was added to gene: CLCNKA.
Childhood onset dystonia, chorea or related movement disorder v3.36 SLC18A2 Achchuthan Shanmugasundram Classified gene: SLC18A2 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.36 SLC18A2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence (at least four unrelated cases and functional evidence) available for the association of this gene to movement disorders including dystonia. Hence, this gene can be promoted to green rating at the next GMS review.
Childhood onset dystonia, chorea or related movement disorder v3.36 SLC18A2 Achchuthan Shanmugasundram Gene: slc18a2 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.35 SLC18A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC18A2 were changed from Brain Dopamine Serotonin Vesicular Transport Disease (Other disorders of neurotransmitter metabolism); Vesicular monoamine transporter deficiency to ?Parkinsonism-dystonia, infantile, 2, OMIM:618049
Childhood onset dystonia, chorea or related movement disorder v3.34 SLC18A2 Achchuthan Shanmugasundram Publications for gene: SLC18A2 were set to 27830117; 28477711; 26497564; 23363473; 27520881; 24398404; 24018103; 27604308
Childhood onset dystonia, chorea or related movement disorder v3.33 SLC18A2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: SLC18A2.
Childhood onset dystonia, chorea or related movement disorder v3.33 SLC18A2 Achchuthan Shanmugasundram changed review comment from: PMID:23363473 - Eight children from an extended consanguineous Saudi Arabian family had a complex neurological disorder apparent since infancy. This disorder is characterised by abnormal movements, including parkinsonism, dystonia, and poor fine motor skills, as well as autonomic dysfunction, including abnormal sweating, cold extremities, and poor sleep. They were identified with a homozygous SLC18A2 variant (p.Pro387Leu). Functional evaluation showed that protein harbouring this variant has dramatically reduced activity than wild type protein, suggesting severe, but not complete loss of function as mechanism of action.

PMID:26497564 - Two male siblings from a consanguineous fancy was reported with a disorder comprising truncal hypotonia, a general paucity of movements, extrapyramidal signs and cognitive delay. They were identified with a homozygous SLC18A2 variant (p.Pro237His).; to: PMID:23363473 - Eight children from an extended consanguineous Saudi Arabian family had a complex neurological disorder apparent since infancy. This disorder is characterised by abnormal movements, including parkinsonism, dystonia, and poor fine motor skills, as well as autonomic dysfunction, including abnormal sweating, cold extremities, and poor sleep. They were identified with a homozygous SLC18A2 variant (p.Pro387Leu). Functional evaluation showed that protein harbouring this variant has dramatically reduced activity than wild type protein, suggesting severe, but not complete loss of function as mechanism of action.

PMID:26497564 - Two male siblings from a consanguineous family was reported with a disorder comprising truncal hypotonia, a general paucity of movements, extrapyramidal signs and cognitive delay. They were identified with a homozygous SLC18A2 variant (p.Pro237His).

PMID:31240161 - A child from a consanguineous family presented with hypotonia, mental disability, epilepsy, uncontrolled movements, and gastrointestinal problems and was identified with a homozygous SLC18A2 variant (p.Pro316Ala).

PMID:34078222 - A 6-month-old male infant who presented with developmental delay and suspected cerebral palsy was also diagnosed with infantile parkinsonism-dystonia-2 and was identified with the homozygous variant (p.Pro237His) reported in PMID:26497564.

This gene has been associated with relevant phenotypes in OMIM (PMID:618049), but not in Gene2Phenotype.
Childhood onset dystonia, chorea or related movement disorder v3.33 SLC18A2 Achchuthan Shanmugasundram commented on gene: SLC18A2: PMID:23363473 - Eight children from an extended consanguineous Saudi Arabian family had a complex neurological disorder apparent since infancy. This disorder is characterised by abnormal movements, including parkinsonism, dystonia, and poor fine motor skills, as well as autonomic dysfunction, including abnormal sweating, cold extremities, and poor sleep. They were identified with a homozygous SLC18A2 variant (p.Pro387Leu). Functional evaluation showed that protein harbouring this variant has dramatically reduced activity than wild type protein, suggesting severe, but not complete loss of function as mechanism of action.

PMID:26497564 - Two male siblings from a consanguineous fancy was reported with a disorder comprising truncal hypotonia, a general paucity of movements, extrapyramidal signs and cognitive delay. They were identified with a homozygous SLC18A2 variant (p.Pro237His).
Early onset or syndromic epilepsy v4.84 TMEM63B Annalisa Vetro reviewed gene: TMEM63B: Rating: ; Mode of pathogenicity: None; Publications: 37421948; Phenotypes: abnormal myelination, developmental and epileptic encephalopathy, hemolytic anemia, infantile spasms; Mode of inheritance: None
Renal tubulopathies v4.5 CLCNKB Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for CLCNKB should be BIALLELIC, autosomal or pseudoautosomal. Although digenic CLCNKB & CLCNKA variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090), the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Renal tubulopathies v4.5 CLCNKB Sarah Leigh Mode of inheritance for gene: CLCNKB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Renal tubulopathies v4.4 CLCNKB Sarah Leigh Tag monogenic-polygenic tag was added to gene: CLCNKB.
Intellectual disability v5.252 CLCNKB Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for CLCNKB should be BIALLELIC, autosomal or pseudoautosomal. Although digenic CLCNKB & CLCNKA variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090), the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Intellectual disability v5.252 CLCNKB Sarah Leigh Mode of inheritance for gene: CLCNKB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.251 CLCNKB Sarah Leigh Tag digenic was removed from gene: CLCNKB.
Tag monogenic-polygenic tag was added to gene: CLCNKB.
Fetal anomalies v3.103 CLCNKB Sarah Leigh Tag monogenic-polygenic tag was added to gene: CLCNKB.
Fetal anomalies v3.103 CLCNKB Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for CLCNKB should be BIALLELIC, autosomal or pseudoautosomal. Although digenic CLCNKB & CLCNKA variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090), the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Fetal anomalies v3.103 CLCNKB Sarah Leigh Mode of inheritance for gene: CLCNKB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ductal plate malformation v1.25 CLCNKB Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for CLCNKB should be BIALLELIC, autosomal or pseudoautosomal. Although digenic CLCNKB & CLCNKA variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090), the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Ductal plate malformation v1.25 CLCNKB Sarah Leigh Mode of inheritance for gene: CLCNKB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v4.3 CLCNKB Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for CLCNKB should be BIALLELIC, autosomal or pseudoautosomal. Although digenic CLCNKB & CLCNKA variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090), this phenotype is not relevant to this panel and the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Nephrocalcinosis or nephrolithiasis v4.3 CLCNKB Sarah Leigh Mode of inheritance for gene: CLCNKB was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ductal plate malformation v1.24 CLCNKB Sarah Leigh Tag monogenic-polygenic tag was added to gene: CLCNKB.
Nephrocalcinosis or nephrolithiasis v4.2 CLCNKB Sarah Leigh Tag monogenic-polygenic tag was added to gene: CLCNKB.
Tag Q3_23_MOI tag was added to gene: CLCNKB.
Ductal plate malformation v1.24 CLCNKB Sarah Leigh Mode of inheritance for gene: CLCNKB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v4.2 CLCNKB Sarah Leigh reviewed gene: CLCNKB: Rating: GREEN; Mode of pathogenicity: None; Publications: 120550, 9326936, 15717167; Phenotypes: Bartter syndrome, type 3, OMIM:607364, Bartter disease type 3, MONDO:0011822; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v3.33 SLC18A2 Achchuthan Shanmugasundram reviewed gene: SLC18A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23363473, 26497564, 31240161, 34078222; Phenotypes: ?Parkinsonism-dystonia, infantile, 2, OMIM:618049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v3.33 TBC1D24 Achchuthan Shanmugasundram Classified gene: TBC1D24 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.33 TBC1D24 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated cases reported with dystonia as a feature of the overall phenotype. Hence, this gene can be promoted to green rating at the next major update.
Childhood onset dystonia, chorea or related movement disorder v3.33 TBC1D24 Achchuthan Shanmugasundram Gene: tbc1d24 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.32 TBC1D24 Achchuthan Shanmugasundram Phenotypes for gene: TBC1D24 were changed from Epilepsy, rolandic, with proxysmal exercise-induce dystonia and writer's cramp, MIM# 608105 to Epilepsy, rolandic, with paroxysmal exercise-induce dystonia and writer's cramp, OMIM:608105; Developmental and epileptic encephalopathy 16, OMIM:615338
Childhood onset dystonia, chorea or related movement disorder v3.31 TBC1D24 Achchuthan Shanmugasundram Publications for gene: TBC1D24 were set to 31257402
Childhood onset dystonia, chorea or related movement disorder v3.30 TBC1D24 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: TBC1D24.
Childhood onset dystonia, chorea or related movement disorder v3.30 TBC1D24 Achchuthan Shanmugasundram reviewed gene: TBC1D24: Rating: GREEN; Mode of pathogenicity: None; Publications: 21087195, 23343562, 31257402; Phenotypes: Epilepsy, rolandic, with paroxysmal exercise-induce dystonia and writer's cramp, OMIM:608105, Developmental and epileptic encephalopathy 16, OMIM:615338; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v3.30 SYT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are four unrelated cases with dystonia as a feature of the SYT1-associated neurodevelopmental disorder. Hence, this gene should be promoted to green rating at the next major update.; to: Comment on list classification: As reviewed by Zornitza Stark, there are four unrelated cases with dystonia as a feature of Baker-Gordon syndrome. Hence, this gene should be promoted to green rating at the next major update.
Childhood onset dystonia, chorea or related movement disorder v3.30 SYT1 Achchuthan Shanmugasundram Classified gene: SYT1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.30 SYT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are four unrelated cases with dystonia as a feature of the SYT1-associated neurodevelopmental disorder. Hence, this gene should be promoted to green rating at the next major update.
Childhood onset dystonia, chorea or related movement disorder v3.30 SYT1 Achchuthan Shanmugasundram Gene: syt1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.29 SYT1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: SYT1.
Childhood onset dystonia, chorea or related movement disorder v3.29 SYT1 Achchuthan Shanmugasundram reviewed gene: SYT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30107533; Phenotypes: Baker-Gordon syndrome, OMIM:618218; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia, chorea or related movement disorder v3.29 SQSTM1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: SQSTM1.
Childhood onset dystonia, chorea or related movement disorder v3.29 SQSTM1 Achchuthan Shanmugasundram Classified gene: SQSTM1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.29 SQSTM1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated families) available for promoting this gene to green rating at the next major update.
Childhood onset dystonia, chorea or related movement disorder v3.29 SQSTM1 Achchuthan Shanmugasundram Gene: sqstm1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.28 SQSTM1 Achchuthan Shanmugasundram Phenotypes for gene: SQSTM1 were changed from Myopathy, distal, with rimmed vacuoles , MIM#617158 to Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, OMIM:617145
Childhood onset dystonia, chorea or related movement disorder v3.27 SQSTM1 Achchuthan Shanmugasundram reviewed gene: SQSTM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27545679; Phenotypes: Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, OMIM:617145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v3.27 L2HGDH Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: L2HGDH.
Childhood onset dystonia, chorea or related movement disorder v3.27 L2HGDH Achchuthan Shanmugasundram Classified gene: L2HGDH as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.27 L2HGDH Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are four unrelated cases with dystonia as a feature of the condition and hence this gene can be promoted to green rating in the next GMS review.
Childhood onset dystonia, chorea or related movement disorder v3.27 L2HGDH Achchuthan Shanmugasundram Gene: l2hgdh has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.26 L2HGDH Achchuthan Shanmugasundram Mode of inheritance for gene: L2HGDH was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v3.25 L2HGDH Achchuthan Shanmugasundram Phenotypes for gene: L2HGDH were changed from L-2-hydroxyglutaric aciduria, 236792 to L-2-hydroxyglutaric aciduria, OMIM:236792
Childhood onset dystonia, chorea or related movement disorder v3.24 L2HGDH Achchuthan Shanmugasundram Publications for gene: L2HGDH were set to
Childhood onset dystonia, chorea or related movement disorder v3.23 L2HGDH Achchuthan Shanmugasundram reviewed gene: L2HGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 15824270, 18780161, 24753671; Phenotypes: L-2-hydroxyglutaric aciduria, OMIM:236792; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.251 MKL2 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.251 MKL2 Achchuthan Shanmugasundram Classified gene: MKL2 as Amber List (moderate evidence)
Intellectual disability v5.251 MKL2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are only two unrelated cases reported so far, this gene should be rated amber for now.
Intellectual disability v5.251 MKL2 Achchuthan Shanmugasundram Gene: mkl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.250 MKL2 Achchuthan Shanmugasundram Phenotypes for gene: MKL2 were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.250 MKL2 Achchuthan Shanmugasundram Phenotypes for gene: MKL2 were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.250 MKL2 Achchuthan Shanmugasundram Phenotypes for gene: MKL2 were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.249 MKL2 Achchuthan Shanmugasundram Phenotypes for gene: MKL2 were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.249 MKL2 Achchuthan Shanmugasundram Phenotypes for gene: MKL2 were changed from neurodevelopmental phenotype with dysmorphic features to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.249 MKL2 Achchuthan Shanmugasundram Publications for gene: MKL2 were set to 37013900
Intellectual disability v5.249 MKL2 Achchuthan Shanmugasundram Publications for gene: MKL2 were set to 37013900
Intellectual disability v5.248 MKL2 Achchuthan Shanmugasundram Publications for gene: MKL2 were set to 37013900
Intellectual disability v5.248 MKL2 Achchuthan Shanmugasundram Publications for gene: MKL2 were set to PMID:37013900
Intellectual disability v5.247 MKL2 Achchuthan Shanmugasundram commented on gene: MKL2: PMID:37013900 - Two unrelated paediatric cases with de novo variants in MKL2 gene (p.Arg103Gly & p.Ala91Pro) were reported with mild dysmorphic features, severe intellectual disability, global developmental delays, speech apraxia, and impulse control issues. Functional studies in a Drosophila model suggest a gain of function disease mechanism.
Intellectual disability v5.247 MKL2 Achchuthan Shanmugasundram reviewed gene: MKL2: Rating: AMBER; 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: 37013900; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v2.23 AKT3 Arina Puzriakova Phenotypes for gene: AKT3 were changed from Overgrowth syndrome (not always mosaic in this case) to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, OMIM:615937
Mosaic skin disorders - deep sequencing v2.22 AKT3 Arina Puzriakova Publications for gene: AKT3 were set to
Mosaic skin disorders - deep sequencing v2.21 AKT3 Arina Puzriakova Mode of pathogenicity for gene: AKT3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mosaic skin disorders - deep sequencing v2.20 AKT3 Arina Puzriakova Classified gene: AKT3 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.20 AKT3 Arina Puzriakova Added comment: Comment on list classification: Variants in this gene cause a spectrum of megalencephaly-related disorders, which in some cases can present as megalencephaly-capillary malformation syndrome (MCAP). Both somatic and germline variants have been reported. Vascular skin anomalies have been identified in at least 2 individuals with germline variants (PMIDs: 22729224; 23745724) and 5 individuals with somatic variants (PMIDs: 25722288; 28969385; 34237354; 36695285; 37395289) meaning that AKT3 can be promoted to green at the next GMS panel update.
Mosaic skin disorders - deep sequencing v2.20 AKT3 Arina Puzriakova Gene: akt3 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v2.19 AKT3 Arina Puzriakova Tag curated_removed was removed from gene: AKT3.
Tag Q3_23_promote_green tag was added to gene: AKT3.
Tag Q3_23_NHS_review tag was added to gene: AKT3.
Vascular skin disorders v1.52 AKT3 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: AKT3.
Vascular skin disorders v1.52 AKT3 Arina Puzriakova Classified gene: AKT3 as Amber List (moderate evidence)
Vascular skin disorders v1.52 AKT3 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Zornitza Stark (Australian Genomics). Variants in this gene cause a spectrum of megalencephaly-related disorders, which in some cases can present as megalencephaly-capillary malformation syndrome (MCAP). Both somatic and germline variants have been reported. Vascular skin anomalies have been identified in at least 2 individuals germline variants (PMIDs: 22729224; 23745724) and 5 individuals with somatic variants (PMIDs: 25722288; 28969385; 34237354; 36695285; 37395289). Somatic variants may be missed but given that this panel is a possible referral route for these patients, recommending that AKT3 is promoted to green at the next GMS panel update.
Vascular skin disorders v1.52 AKT3 Arina Puzriakova Gene: akt3 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.5 FN1 Eleanor Williams Classified gene: FN1 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v3.5 FN1 Eleanor Williams Added comment: Comment on list classification: Copied this gene from the Proteinuric renal disease panel and added it to the Unexplained young onset end-stage renal disease panel. Changing it to Amber for now, until it has been completely reviewed for suitability for this panel and until the next GMS update review.
Unexplained young onset end-stage renal disease v3.5 FN1 Eleanor Williams Gene: fn1 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.4 FN1 Eleanor Williams Entity copied from Proteinuric renal disease v4.1
Unexplained young onset end-stage renal disease v3.4 FN1 Eleanor Williams gene: FN1 was added
gene: FN1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Green,Expert list
Mode of inheritance for gene: FN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FN1 were set to 18268355; 27056061; 31419955
Phenotypes for gene: FN1 were set to Glomerulopathy with fibronectin deposits 2, OMIM:601894
Intellectual disability v5.247 ATG4D Achchuthan Shanmugasundram Classified gene: ATG4D as Amber List (moderate evidence)
Intellectual disability v5.247 ATG4D Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases with mild cognitive impairment and hence this gene should be rated amber with the current evidence.
Intellectual disability v5.247 ATG4D Achchuthan Shanmugasundram Gene: atg4d has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.246 ATG4D Achchuthan Shanmugasundram changed review comment from: PMID:36765070 - Three individuals from two different families were reported with a neurodevelopmental disorder and identified with compound heterozygous variants in ATG4D gene (family 1: :c.266G>A/ p.Ser89Asn & c.839A>G/ p.Tyr280Cys; family 2: c.1310_1328del/ p.Asp437Alafs*37 & c.1066G>A/ p.Asp356Asn). Patient from family 1 and one of two patients from family 2 had mild cognitive impairment.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'limited' rating in the DD panel), but not yet in OMIM.; to: PMID:36765070 - Three individuals from two different families were reported with a neurodevelopmental disorder and identified with compound heterozygous variants in ATG4D gene (family 1: :c.266G>A/ p.Ser89Asn & c.839A>G/ p.Tyr280Cys; family 2: c.1310_1328del/ p.Asp437Alafs*37 & c.1066G>A/ p.Asp356Asn). Patient from family 1 and one of two patients from family 2 had mild cognitive impairment. Based on the clinical, bioinformatic, and functional data, the authors also concluded that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of syndromic neurodevelopmental disorder.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'limited' rating in the DD panel), but not yet in OMIM.
Intellectual disability v5.246 ATG4D Achchuthan Shanmugasundram changed review comment from: PMID:36765070 - Three individuals from two different families were reported with a neurodevelopmental disorder and identified with compound heterozygous variants in ATG4D gene (family 1: :c.266G>A/ p.Ser89Asn & c.839A>G/ p.Tyr280Cys; family 2: c.1310_1328del/ p.Asp437Alafs*37 & c.1066G>A/ p.Asp356Asn). Patient from family 1 and one of two patients from family 2 had cognitive impairment.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'limited' rating in the DD panel), but not yet in OMIM.; to: PMID:36765070 - Three individuals from two different families were reported with a neurodevelopmental disorder and identified with compound heterozygous variants in ATG4D gene (family 1: :c.266G>A/ p.Ser89Asn & c.839A>G/ p.Tyr280Cys; family 2: c.1310_1328del/ p.Asp437Alafs*37 & c.1066G>A/ p.Asp356Asn). Patient from family 1 and one of two patients from family 2 had mild cognitive impairment.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'limited' rating in the DD panel), but not yet in OMIM.
Intellectual disability v5.246 ATG4D Achchuthan Shanmugasundram Phenotypes for gene: ATG4D were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.246 ATG4D Achchuthan Shanmugasundram Phenotypes for gene: ATG4D were changed from neurodevelopmental disorder characterized by speech and motor impairment to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.245 ATG4D Achchuthan Shanmugasundram edited their review of gene: ATG4D: Changed rating: AMBER; Changed publications to: 36765070; Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.84 AKT3 Arina Puzriakova Publications for gene: AKT3 were set to
Early onset or syndromic epilepsy v4.83 AKT3 Arina Puzriakova Phenotypes for gene: AKT3 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 615937 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, OMIM:615937
Intellectual disability v5.245 AKT3 Arina Puzriakova Phenotypes for gene: AKT3 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, 603387; HEMIMEGALENCEPHALY AKT3 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, OMIM:615937
Intellectual disability v5.244 ATG4D Achchuthan Shanmugasundram commented on gene: ATG4D
Neurological segmental overgrowth v2.7 AKT3 Arina Puzriakova Tag mosaicism tag was added to gene: AKT3.
Fetal anomalies v3.102 AKT3 Arina Puzriakova Phenotypes for gene: AKT3 were changed from HEMIMEGALENCEPHALY AKT3 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, OMIM:615937
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.120 AKT3 Arina Puzriakova Phenotypes for gene: AKT3 were changed from Human overgrowth syndrome type; Overgrowth with Intellectual disability to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, OMIM:615937
Malformations of cortical development v4.4 AKT3 Arina Puzriakova Phenotypes for gene: AKT3 were changed from Polymicrogyria, macrocephaly to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, OMIM:615937
Segmental overgrowth disorders - Deep sequencing v3.13 AKT3 Arina Puzriakova Phenotypes for gene: AKT3 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, 615937; MPPH2; Macrocephaly and Overgrowth Syndromes; Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus syndrome 2 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, OMIM:615937; Macrocephaly and Overgrowth Syndromes
Proteinuric renal disease v4.1 FN1 Eleanor Williams commented on gene: FN1: Looking at reports of End-stage renal disease and the age of onset:

PMID: 18268355 - Castelletti et al 2008 - 3 members of the same extended family are reported to have ESRF at ages 74, 32 and 34.
PMID: 27056061- Ohtsubo et al 2016 - 1 patient with ESRD at 34 years, and one other at age 49.
PMID: 31419955 - Gonçalves Dos Reis Monteiro et al 2019 - the father and son reported do not appear to have ESRD.
Intellectual disability v5.244 PSMC3 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.244 PSMC3 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.244 PSMC3 Achchuthan Shanmugasundram Classified gene: PSMC3 as Amber List (moderate evidence)
Intellectual disability v5.244 PSMC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene can be promoted to green rating at the next GMS review.
Intellectual disability v5.244 PSMC3 Achchuthan Shanmugasundram Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.243 PSMC3 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence for the association of monoallelic variants from this gene with intellectual disability. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Intellectual disability v5.243 PSMC3 Achchuthan Shanmugasundram Mode of inheritance for gene: PSMC3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.243 PSMC3 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence for the association of monoallelic variants from this gene with intellectual disability. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Intellectual disability v5.243 PSMC3 Achchuthan Shanmugasundram Mode of inheritance for gene: PSMC3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.243 PSMC3 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence for the association of monoallelic variants from this gene with intellectual disability. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Intellectual disability v5.243 PSMC3 Achchuthan Shanmugasundram Mode of inheritance for gene: PSMC3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PSMC3.
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.242 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.241 PSMC3 Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from neurodevelopmental delay to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v5.241 PSMC3 Achchuthan Shanmugasundram Publications for gene: PSMC3 were set to 32500975; 37256937
Intellectual disability v5.241 PSMC3 Achchuthan Shanmugasundram Publications for gene: PSMC3 were set to 32500975; 37256937
Intellectual disability v5.241 PSMC3 Achchuthan Shanmugasundram Publications for gene: PSMC3 were set to 32500975; 37256937
Intellectual disability v5.240 PSMC3 Achchuthan Shanmugasundram Publications for gene: PSMC3 were set to 32500975; 37256937
Intellectual disability v5.240 PSMC3 Achchuthan Shanmugasundram Publications for gene: PSMC3 were set to PMID: 37256937
Intellectual disability v5.239 PSMC3 Achchuthan Shanmugasundram reviewed gene: PSMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32500975, 37256937; Phenotypes: ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Segmental overgrowth disorders - Deep sequencing v3.12 AKT2 Arina Puzriakova Classified gene: AKT2 as Amber List (moderate evidence)
Segmental overgrowth disorders - Deep sequencing v3.12 AKT2 Arina Puzriakova Added comment: Comment on list classification: At least three unrelated families reported with the same activating mosaic c.49G>A (p.E17K) variant in the AKT2 gene. Mild asymmetric overgrowth was seen in 2/3 cases. Sibs from the third family showed early overgrowth but no signs of body asymmetry. Overall the evidence is borderline amber/green. However, as this gene has been expert reviewed as green by Tom Cullup (GOSH) and is likely to be diagnostically relevant, recommending AKT2 is promoted to green status at the next GMS panel update.
Segmental overgrowth disorders - Deep sequencing v3.12 AKT2 Arina Puzriakova Gene: akt2 has been classified as Amber List (Moderate Evidence).
Segmental overgrowth disorders - Deep sequencing v3.11 AKT2 Arina Puzriakova Publications for gene: AKT2 were set to 28502730
Segmental overgrowth disorders - Deep sequencing v3.10 AKT2 Arina Puzriakova Mode of pathogenicity for gene: AKT2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Segmental overgrowth disorders - Deep sequencing v3.9 AKT2 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: AKT2.
Tag Q3_23_NHS_review tag was added to gene: AKT2.
Tag recurrent-variant tag was added to gene: AKT2.
Mosaic skin disorders - deep sequencing v2.19 PIK3R1 Arina Puzriakova Publications for gene: PIK3R1 were set to PMID: 34040190; 35964931
Mosaic skin disorders - deep sequencing v2.18 PIK3R1 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: PIK3R1.
Tag Q3_23_NHS_review tag was added to gene: PIK3R1.
Segmental overgrowth disorders - Deep sequencing v3.9 PIK3R1 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: PIK3R1.
Tag Q3_23_NHS_review tag was added to gene: PIK3R1.
Segmental overgrowth disorders - Deep sequencing v3.9 PIK3R1 Arina Puzriakova Publications for gene: PIK3R1 were set to PMID: 34040190; 35964931
Mosaic skin disorders - deep sequencing v2.18 PIK3R1 Arina Puzriakova Classified gene: PIK3R1 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.18 PIK3R1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). There is sufficient evidence to promote this gene to green at the next GMS panel update. At least 17 cases have been identified with somatic mosaic variants in PIK3R1 (PMIDs: 34040190; 35964931). Affected individuals exhibit various vascular lesions and overgrowth which were comparable to features of the PIK3CA-related overgrowth spectrum.
Mosaic skin disorders - deep sequencing v2.18 PIK3R1 Arina Puzriakova Gene: pik3r1 has been classified as Amber List (Moderate Evidence).
Segmental overgrowth disorders - Deep sequencing v3.8 PIK3R1 Arina Puzriakova Classified gene: PIK3R1 as Amber List (moderate evidence)
Segmental overgrowth disorders - Deep sequencing v3.8 PIK3R1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). There is sufficient evidence to promote this gene to green at the next GMS panel update. At least 17 cases have been identified with somatic mosaic variants in PIK3R1 (PMIDs: 34040190; 35964931). Affected individuals exhibit various vascular lesions and overgrowth which were comparable to features of the PIK3CA-related overgrowth spectrum.
Segmental overgrowth disorders - Deep sequencing v3.8 PIK3R1 Arina Puzriakova Gene: pik3r1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.239 KCNH5 Achchuthan Shanmugasundram Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Intellectual disability v5.240 KCNH5 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.240 KCNH5 Achchuthan Shanmugasundram Classified gene: KCNH5 as Amber List (moderate evidence)
Intellectual disability v5.240 KCNH5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence for the association of this gene to intellectual disability. Hence, this gene can be promoted to green rating at the next GMS review.
Intellectual disability v5.240 KCNH5 Achchuthan Shanmugasundram Gene: kcnh5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.241 KCNH5 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.241 KCNH5 Achchuthan Shanmugasundram Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Intellectual disability v5.241 KCNH5 Achchuthan Shanmugasundram Classified gene: KCNH5 as Amber List (moderate evidence)
Intellectual disability v5.241 KCNH5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence for the association of this gene to intellectual disability. Hence, this gene can be promoted to green rating at the next GMS review.
Intellectual disability v5.241 KCNH5 Achchuthan Shanmugasundram Gene: kcnh5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.240 KCNH5 Achchuthan Shanmugasundram Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Intellectual disability v5.240 KCNH5 Achchuthan Shanmugasundram Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Intellectual disability v5.240 KCNH5 Achchuthan Shanmugasundram Classified gene: KCNH5 as Amber List (moderate evidence)
Intellectual disability v5.240 KCNH5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence for the association of this gene to intellectual disability. Hence, this gene can be promoted to green rating at the next GMS review.
Intellectual disability v5.240 KCNH5 Achchuthan Shanmugasundram Gene: kcnh5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.239 KCNH5 Achchuthan Shanmugasundram Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Intellectual disability v5.239 KCNH5 Achchuthan Shanmugasundram Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Intellectual disability v5.239 KCNH5 Achchuthan Shanmugasundram Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Intellectual disability v5.240 KCNH5 Achchuthan Shanmugasundram Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Intellectual disability v5.239 KCNH5 Achchuthan Shanmugasundram Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Intellectual disability v5.240 KCNH5 Achchuthan Shanmugasundram Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Intellectual disability v5.239 KCNH5 Achchuthan Shanmugasundram Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Intellectual disability v5.239 KCNH5 Achchuthan Shanmugasundram Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Intellectual disability v5.239 KCNH5 Achchuthan Shanmugasundram Phenotypes for gene: KCNH5 were changed from INFANTILE EPILEPTIC ENCEPHALOPATHY to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Intellectual disability v5.238 KCNH5 Achchuthan Shanmugasundram Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Intellectual disability v5.239 KCNH5 Achchuthan Shanmugasundram Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Intellectual disability v5.238 KCNH5 Achchuthan Shanmugasundram Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Intellectual disability v5.238 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 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
Intellectual disability v5.238 KCNH5 Achchuthan Shanmugasundram Publications for gene: KCNH5 were set to 23647072
Intellectual disability v5.238 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 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
Intellectual disability v5.238 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 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
Intellectual disability v5.237 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.236 KCNH5 Achchuthan Shanmugasundram Mode of inheritance for gene: KCNH5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.236 KCNH5 Achchuthan Shanmugasundram Mode of inheritance for gene: KCNH5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v5.235 KCNH5 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: KCNH5.
Intellectual disability v5.235 KCNH5 Achchuthan Shanmugasundram reviewed gene: KCNH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23647072, 35874597, 36307226, 24133262; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100062, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.82 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 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
Early onset or syndromic epilepsy v4.81 KCNH5 Achchuthan Shanmugasundram Publications for gene: KCNH5 were set to 24133262; 23647072
Early onset or syndromic epilepsy v4.80 KCNH5 Achchuthan Shanmugasundram Phenotypes for gene: KCNH5 were changed from epilepsy to developmental and epileptic encephalopathy, MONDO:0100062; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.79 KCNH5 Achchuthan Shanmugasundram Mode of inheritance for gene: KCNH5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.78 KCNH5 Achchuthan Shanmugasundram Classified gene: KCNH5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.78 KCNH5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence for the association of this gene to epilepsy. Hence, this gene can be promoted to green rating at the next GMS review.
Early onset or syndromic epilepsy v4.78 KCNH5 Achchuthan Shanmugasundram Gene: kcnh5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.77 KCNH5 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: KCNH5.
Early onset or syndromic epilepsy v4.77 KCNH5 Achchuthan Shanmugasundram reviewed gene: KCNH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23647072, 35874597, 36307226, 24133262; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100062, epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v4.15 SETD5 Achchuthan Shanmugasundram Phenotypes for gene: SETD5 were changed from Intellectual developmental disorder, autosomal dominant 23, OMIM:615761; Skeletal dysplasia; intellectual disability; developmental delay; facial dysmorphism to Intellectual developmental disorder, autosomal dominant 23, OMIM:615761; skeletal dysplasia, MONDO:0018230; facial dysmorphism
Skeletal dysplasia v4.14 SETD5 Achchuthan Shanmugasundram edited their review of gene: SETD5: Changed phenotypes to: Intellectual developmental disorder, autosomal dominant 23, OMIM:615761, skeletal dysplasia, MONDO:0018230
Skeletal dysplasia v4.14 SETD5 Achchuthan Shanmugasundram Deleted their comment
Skeletal dysplasia v4.14 SETD5 Achchuthan Shanmugasundram Classified gene: SETD5 as Amber List (moderate evidence)
Skeletal dysplasia v4.14 SETD5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Tracy Lester, the observed intellectual developmental disorder phenotype includes skeletal abnormalities ( at least 9 cases) and these might appear before ID. Hence, this gene can be promoted to green rating in the next GMS review.
Skeletal dysplasia v4.14 SETD5 Achchuthan Shanmugasundram Gene: setd5 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.13 SETD5 Achchuthan Shanmugasundram Classified gene: SETD5 as Amber List (moderate evidence)
Skeletal dysplasia v4.13 SETD5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Tracy Lester, the observed intellectual developmental disorder phenotype includes skeletal abnormalities ( at least 9 cases) and these might appear before ID. Hence, this gene can be promoted to green rating in the next GMS review.
Skeletal dysplasia v4.13 SETD5 Achchuthan Shanmugasundram Gene: setd5 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.12 SETD5 Achchuthan Shanmugasundram Phenotypes for gene: SETD5 were changed from Skeletal dysplasia; intellectual disability; developmental delay; facial dysmorphism to Intellectual developmental disorder, autosomal dominant 23, OMIM:615761; Skeletal dysplasia; intellectual disability; developmental delay; facial dysmorphism
Skeletal dysplasia v4.11 SETD5 Achchuthan Shanmugasundram Publications for gene: SETD5 were set to 28881385
Skeletal dysplasia v4.10 SETD5 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: SETD5.
Tag Q3_23_NHS_review tag was added to gene: SETD5.
Skeletal dysplasia v4.10 SETD5 Achchuthan Shanmugasundram reviewed gene: SETD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 24680889, 28881385; Phenotypes: Intellectual developmental disorder, autosomal dominant 23, OMIM:615761; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v3.28 ELAC2 Achchuthan Shanmugasundram Classified gene: ELAC2 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v3.28 ELAC2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Matthew Edwards, there is sufficient evidence for the promotion of this gene to green rating in the next GMS review.
Paediatric or syndromic cardiomyopathy v3.28 ELAC2 Achchuthan Shanmugasundram Gene: elac2 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v3.27 ELAC2 Achchuthan Shanmugasundram Phenotypes for gene: ELAC2 were changed from to Combined oxidative phosphorylation deficiency 17, OMIM:615440
Paediatric or syndromic cardiomyopathy v3.26 ELAC2 Achchuthan Shanmugasundram Publications for gene: ELAC2 were set to PMID: 23849775
Paediatric or syndromic cardiomyopathy v3.25 ELAC2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: ELAC2.
Tag Q3_23_NHS_review tag was added to gene: ELAC2.
Paediatric or syndromic cardiomyopathy v3.25 ELAC2 Achchuthan Shanmugasundram reviewed gene: ELAC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23849775; Phenotypes: Combined oxidative phosphorylation deficiency 17, OMIM:615440; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v2.14 PPA2 Achchuthan Shanmugasundram Classified gene: PPA2 as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v2.14 PPA2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Matthew Edwards, there is sufficient evidence for this gene to be promoted to green rating at the next GMS review.
Dilated and arrhythmogenic cardiomyopathy v2.14 PPA2 Achchuthan Shanmugasundram Gene: ppa2 has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v2.13 PPA2 Achchuthan Shanmugasundram Phenotypes for gene: PPA2 were changed from Sudden cardiac failure, infantile; Sudden cardiac failure, alcohol-induced to Sudden cardiac failure, infantile, OMIM:617222; ?Sudden cardiac failure, alcohol-induced, OMIM:617223
Dilated and arrhythmogenic cardiomyopathy v2.12 PPA2 Achchuthan Shanmugasundram Publications for gene: PPA2 were set to PMID: 34400813
Dilated and arrhythmogenic cardiomyopathy v2.11 PPA2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PPA2.
Tag Q3_23_NHS_review tag was added to gene: PPA2.
Dilated and arrhythmogenic cardiomyopathy v2.11 PPA2 Achchuthan Shanmugasundram reviewed gene: PPA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34400813; Phenotypes: Sudden cardiac failure, infantile, OMIM:617222, ?Sudden cardiac failure, alcohol-induced, OMIM:617223; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.235 CLCNKB Sarah Leigh Tag polygenic was removed from gene: CLCNKB.
Tag digenic tag was added to gene: CLCNKB.
Intellectual disability v5.235 CLCNKB Sarah Leigh Phenotypes for gene: CLCNKB were changed from Bartter syndrome, type 3, 607364Bartter syndrome, type 4b, digenic, 613090; BARTTER SYNDROME TYPE 4B to Bartter syndrome, type 3, OMIM:607364; Bartter disease type 3, MONDO:0011822; Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 4B, MONDO:0000909
Fetal anomalies v3.101 CLCNKB Sarah Leigh Phenotypes for gene: CLCNKB were changed from BARTTER SYNDROME TYPE 4B to Bartter syndrome, type 3, OMIM:607364; Bartter disease type 3, MONDO:0011822; Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 4B, MONDO:0000909
Ductal plate malformation v1.23 CLCNKB Sarah Leigh Phenotypes for gene: CLCNKB were changed from Bartter syndrome, type 3 (607364); Bartter syndrome, type 4b, digenic (613090) to Bartter syndrome, type 3, OMIM:607364; Bartter disease type 3, MONDO:0011822; Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 4B, MONDO:0000909
Nephrocalcinosis or nephrolithiasis v4.2 CLCNKB Sarah Leigh Phenotypes for gene: CLCNKB were changed from Bartter syndrome, type 3, 607364; Type 3 Bartter syndrome; Bartter syndrome, type 4b, digenic, 613090; BARTTER SYNDROME TYPE 4B to Bartter syndrome, type 3, OMIM:607364; Bartter disease type 3, MONDO:0011822; Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 4B, MONDO:0000909
Renal tubulopathies v4.4 CLCNKB Sarah Leigh Phenotypes for gene: CLCNKB were changed from Bartter syndrome, type 3, OMIM:607364; Bartter syndrome, type 4b, digenic, OMIM:613090 to Bartter syndrome, type 3, OMIM:607364; Bartter disease type 3, MONDO:0011822; Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 4B, MONDO:0000909
Renal tubulopathies v4.3 CLCNKB Sarah Leigh Deleted their comment
Adult onset leukodystrophy v3.16 GCDH Sarah Leigh Tag Q3_23_promote_green tag was added to gene: GCDH.
Tag Q3_23_MOI tag was added to gene: GCDH.
Adult onset leukodystrophy v3.16 GCDH Sarah Leigh edited their review of gene: GCDH: Added comment: GCDH variants are associated with Glutaricaciduria, type I (OMIM:231670) and as definitive Gen2Phen gene for the same condition. Although OMIM:231670 usually manifests in infancy, four unrelated cases, including white matter involvement, have been reported with an age of onset of 16 to 35 years (15985591;12473778; https://doi.org/10.1002/mds.10442).; Changed rating: GREEN; Changed publications to: 15985591, 12473778, https://doi.org/10.1002/mds.10442; Changed phenotypes to: Glutaricaciduria, type I, OMIM:231670; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset leukodystrophy v3.16 GCDH Sarah Leigh Added comment: Comment on publications: Publication not in PUBMED: https://doi.org/10.1002/mds.10442 "Hand tremor and orofacial dyskinesia: Clinical manifestations of glutaric aciduria type I in a young girl"
Emilio Fernández-Álvarez MD, PhD, Angeles García-Cazorla MD, Anna Sans MD, Cristina Boix PhD, María Antonia Vilaseca PhD, Christianne Busquets PhD, Antonia Ribes PhD
First published: 01 April 2003
Adult onset leukodystrophy v3.16 GCDH Sarah Leigh Publications for gene: GCDH were set to 15985591
Mosaic skin disorders - deep sequencing v2.17 NEK9 Arina Puzriakova Tag somatic tag was added to gene: NEK9.
Mosaic skin disorders - deep sequencing v2.17 NEK9 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Tom Cullup (GOSH). There is sufficient evidence to promote this gene to green at the next GMS panel update. At least five unrelated individuals reported with nevus comedonicus due to somatic mosaic variants in the NEK9 gene. Two individuals had other syndromic features - congenital cataract was the only common finding present in both cases.; to: Comment on list classification: New gene added by Tom Cullup (GOSH). There is sufficient evidence to promote this gene to green at the next GMS panel update. At least five unrelated individuals reported with nevus comedonicus due to somatic mosaic variants in the NEK9 gene. Two individuals had other syndromic features - congenital cataract was the only common finding present in both cases (PMIDs: 27153399; 34184242; 31961058)
Mosaic skin disorders - deep sequencing v2.17 NEK9 Arina Puzriakova Publications for gene: NEK9 were set to PMID: 27153399; 34184242; 33481271
Mosaic skin disorders - deep sequencing v2.16 NEK9 Arina Puzriakova Classified gene: NEK9 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.16 NEK9 Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). There is sufficient evidence to promote this gene to green at the next GMS panel update. At least five unrelated individuals reported with nevus comedonicus due to somatic mosaic variants in the NEK9 gene. Two individuals had other syndromic features - congenital cataract was the only common finding present in both cases.
Mosaic skin disorders - deep sequencing v2.16 NEK9 Arina Puzriakova Gene: nek9 has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.47 BLM Achchuthan Shanmugasundram Classified gene: BLM as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.47 BLM Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with severe insulin resistance and hence it can be promoted to green rating at the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.47 BLM Achchuthan Shanmugasundram Gene: blm has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.46 BLM Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: BLM.
Tag Q3_23_NHS_review tag was added to gene: BLM.
Severe insulin resistance and lipodystrophy syndromes v4.46 BLM Achchuthan Shanmugasundram Publications for gene: BLM were set to 7585968; 16763388; 21536711; 27710244; 2823277; 2947793
Severe insulin resistance and lipodystrophy syndromes v4.45 BLM Achchuthan Shanmugasundram edited their review of gene: BLM: Changed publications to: 7585968, 16763388, 21536711, 27710244, 28232778, 29477938
Severe insulin resistance and lipodystrophy syndromes v4.45 BLM Achchuthan Shanmugasundram edited their review of gene: BLM: Changed publications to: 7585968, 16763388, 21536711, 27710244, 28232778, 2947793
Severe insulin resistance and lipodystrophy syndromes v4.45 BLM Achchuthan Shanmugasundram Publications for gene: BLM were set to 7585968; 16763388; 2153671; 27710244; 2823277; 2947793
Severe insulin resistance and lipodystrophy syndromes v4.44 BLM Achchuthan Shanmugasundram edited their review of gene: BLM: Changed publications to: 7585968, 16763388, 21536711, 27710244, 2823277, 2947793
Severe insulin resistance and lipodystrophy syndromes v4.44 BLM Achchuthan Shanmugasundram Publications for gene: BLM were set to
Severe insulin resistance and lipodystrophy syndromes v4.43 BLM Achchuthan Shanmugasundram Phenotypes for gene: BLM were changed from Bloom Syndrome, severe insulin resistance to Bloom syndrome, OMIM:210900; Insulin resistance, HP:0000855
Mosaic skin disorders - deep sequencing v2.15 NEK9 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: NEK9.
Tag Q3_23_NHS_review tag was added to gene: NEK9.
Severe insulin resistance and lipodystrophy syndromes v4.42 BLM Achchuthan Shanmugasundram edited their review of gene: BLM: Added comment: Insulin resistance was observed in six individuals and lipid profile abnormalities were reported in five of ten individuals with Bloom syndrome (PMID:16763388).; Changed rating: GREEN; Changed publications to: 7585968, 16763388, 2153671, 27710244, 2823277, 2947793
Mosaic skin disorders - deep sequencing v2.15 NEK9 Arina Puzriakova Phenotypes for gene: NEK9 were changed from nevus comedonicus (NC) (MIM: 617025) to Nevus comedonicus, somatic, OMIM:617025
Adult onset leukodystrophy v3.15 GCDH Sarah Leigh Phenotypes for gene: GCDH were changed from Glutaric aciduria, type I 231670 to Glutaricaciduria, type I, OMIM:231670; glutaryl-CoA dehydrogenase deficiency, MONDO:0009281
Adult onset leukodystrophy v3.14 GCDH Sarah Leigh Classified gene: GCDH as Amber List (moderate evidence)
Adult onset leukodystrophy v3.14 GCDH Sarah Leigh Gene: gcdh has been classified as Amber List (Moderate Evidence).
Adult onset leukodystrophy v3.13 RNF216 Sarah Leigh Classified gene: RNF216 as Green List (high evidence)
Adult onset leukodystrophy v3.13 RNF216 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN on this panel at the next major review.
Adult onset leukodystrophy v3.13 RNF216 Sarah Leigh Gene: rnf216 has been classified as Green List (High Evidence).
Adult onset leukodystrophy v3.12 RNF216 Sarah Leigh Tag Q3_23_demote_amber tag was added to gene: RNF216.
Adult onset leukodystrophy v3.12 RNF216 Sarah Leigh changed review comment from: RNF216 variants are associated with Cerebellar ataxia and hypogonadotropic hypogonadism (OMIM:212840), previously known as Gordon Holmes syndrome (GDHS). No phenotype was associated with RNF216 in Gen2Phen.
At least six variants have been reported in four unrelated cases of OMIM:212840. Three of these variants, in four individuals from two unrelated families, have been associated with a variant of GDHS. The variant GDHS includes Huntingtons-like features including white matter lesions (PMID: 16691578).; to: RNF216 variants are associated with Cerebellar ataxia and hypogonadotropic hypogonadism (OMIM:212840), previously known as Gordon Holmes syndrome (GDHS). No phenotype was associated with RNF216 in Gen2Phen.
At least six variants have been reported in four unrelated cases of OMIM:212840. Three of these variants, in four individuals from two unrelated families, have been associated with a variant of GDHS. The variant GDHS includes Huntingtons-like features including white matter lesions (PMID: 25841028).
Adult onset leukodystrophy v3.12 RNF216 Sarah Leigh reviewed gene: RNF216: Rating: AMBER; Mode of pathogenicity: None; Publications: 25841028; Phenotypes: ; Mode of inheritance: None
Adult onset leukodystrophy v3.12 RNF216 Sarah Leigh Phenotypes for gene: RNF216 were changed from Cerebellar ataxia and hypogonadotropic hypogonadism, 212840 to Cerebellar ataxia and hypogonadotropic hypogonadism, OMIM:212840
Severe insulin resistance and lipodystrophy syndromes v4.42 PSMA3 Achchuthan Shanmugasundram Classified gene: PSMA3 as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.42 PSMA3 Achchuthan Shanmugasundram Gene: psma3 has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.41 PSMA3 Achchuthan Shanmugasundram Publications for gene: PSMA3 were set to
Severe insulin resistance and lipodystrophy syndromes v4.40 PSMA3 Achchuthan Shanmugasundram Tag digenic tag was added to gene: PSMA3.
Severe insulin resistance and lipodystrophy syndromes v4.40 PSMA3 Achchuthan Shanmugasundram changed review comment from: PMID:26524591 - Two unrelated cases with heterozygous variants in PSMA3 and PSMB8 were reported with proteasome-associated autoinflammatory syndrome (PRAAS) that includes lipodystrophy and lipid abnormalities. In addition, it was revealed from functional studies that these variants affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity.

This gene has not been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:26524591 - Two unrelated cases with heterozygous variants in PSMA3 and PSMB8 were reported with proteasome-associated autoinflammatory syndrome (PRAAS) that includes lipodystrophy and lipid abnormalities. In addition, it was revealed from functional studies that these variants affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity.

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

The 'digenic' tag has been added as both reported cases had variants in PSMB8 in addition to PSMA3 variants.
Severe insulin resistance and lipodystrophy syndromes v4.40 PSMA3 Achchuthan Shanmugasundram edited their review of gene: PSMA3: Added comment: PMID:26524591 - Two unrelated cases with heterozygous variants in PSMA3 and PSMB8 were reported with proteasome-associated autoinflammatory syndrome (PRAAS) that includes lipodystrophy and lipid abnormalities. In addition, it was revealed from functional studies that these variants affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity.

This gene has not been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; Changed rating: AMBER; Changed publications to: 26524591
Adult onset leukodystrophy v3.11 RNF216 Sarah Leigh Publications for gene: RNF216 were set to 27159321; 25527826; 28334938; 20301621; 24357685
Severe insulin resistance and lipodystrophy syndromes v4.40 PSMA3 Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: These autoinflammatory syndromes include a lipodystrophy (partial and generalised have both been reported) and are caused either by biallelic loss of function mutations in PSMB4 or PSMB8 (PMID: 26524591, 34416217) or by digenic heterozygous mutations in other proteasome encoding genes (PSMB8, PMSA3 PMID: 26524591). PSMB9 has also been implicated in digenic cases but this is in a single familes and lipodystrophy is not reported in the autoinflammatory syndrome of carriers of biallelic loss of function mutations in PSMB9. Only DIGENIC cases of CANDLES involving PSMA3 have been reported.; to: This gene was added on recommendation of NHSE Genomic Medicine Service:
These autoinflammatory syndromes include a lipodystrophy (partial and generalised have both been reported) and are caused either by biallelic loss of function mutations in PSMB4 or PSMB8 (PMID: 26524591, 34416217) or by digenic heterozygous mutations in other proteasome encoding genes (PSMB8, PMSA3 PMID: 26524591).

PSMB9 has also been implicated in digenic cases but this is in a single familes and lipodystrophy is not reported in the autoinflammatory syndrome of carriers of biallelic loss of function mutations in PSMB9. Only DIGENIC cases of CANDLES involving PSMA3 have been reported.
Adult onset leukodystrophy v3.10 RPS6KA3 Sarah Leigh Classified gene: RPS6KA3 as Green List (high evidence)
Adult onset leukodystrophy v3.10 RPS6KA3 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN at the next major review.
Adult onset leukodystrophy v3.10 RPS6KA3 Sarah Leigh Gene: rps6ka3 has been classified as Green List (High Evidence).
Adult onset leukodystrophy v3.9 RPS6KA3 Sarah Leigh Tag Q3_23_demote_red tag was added to gene: RPS6KA3.
Adult onset leukodystrophy v3.9 RPS6KA3 Sarah Leigh edited their review of gene: RPS6KA3: Changed publications to: 16691578
Adult onset leukodystrophy v3.9 RPS6KA3 Sarah Leigh reviewed gene: RPS6KA3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe insulin resistance and lipodystrophy syndromes v4.40 PSMB8 Achchuthan Shanmugasundram changed review comment from: The 'digenic' tag has been added as there are two cases reported with heterozygous variants from both PSMB4 and PSMB8 in addition to patients with homozygous PSMB8 variants.; to: The 'digenic' tag has been added as there are four digenic cases reported (two cases each with heterozygous variants in PSMA3/ PSMB8 and PSMB4/ PSMB8) in addition to patients with homozygous PSMB8 variants.
Severe insulin resistance and lipodystrophy syndromes v4.40 PSMB4 Achchuthan Shanmugasundram changed review comment from: PMID:26524591 - One case with compound heterozygous variants in PSMB4 (monogenic), two cases with heterozygous variants in PSMA3 and PSMB8 (digenic) and two cases with heterozygous variants in PSMB4 and PSMB8 (digenic) were reported with proteasome-associated autoinflammatory syndrome (PRAAS) that includes lipodystrophy and lipid abnormalities. In addition, it was revealed from functional studies that these variants affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity.

PMID:34416217 - A boy with treatment-resistant cutaneous vasculitis was identified with novel heterozygous variants in PSMB4. This patient developed mild lipodystrophy after the successful second hematopoietic stem cell transplantation (HSCT).

This gene has been associated with PRAAS in OMIM and it includes lipodystrophy as one of the clinical manifestations.; to: PMID:26524591 - One case with compound heterozygous variants in PSMB4 (monogenic), two cases with heterozygous variants in PSMB4 and PSMB8 (digenic) and two cases with heterozygous variants in PSMB4 and PSMB9 (digenic) were reported with proteasome-associated autoinflammatory syndrome (PRAAS) that includes lipodystrophy and lipid abnormalities. In addition, it was revealed from functional studies that these variants affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity.

PMID:34416217 - A boy with treatment-resistant cutaneous vasculitis was identified with novel heterozygous variants in PSMB4. This patient developed mild lipodystrophy after the successful second hematopoietic stem cell transplantation (HSCT).

This gene has been associated with PRAAS in OMIM and it includes lipodystrophy as one of the clinical manifestations.
Severe insulin resistance and lipodystrophy syndromes v4.40 PSMB4 Achchuthan Shanmugasundram commented on gene: PSMB4: The 'digenic' tag has been added as there are four additional cases with heterozygous PSMB4 variants and heterozygous variants in either PSMA3 and PSMB8.
Severe insulin resistance and lipodystrophy syndromes v4.40 PSMB4 Achchuthan Shanmugasundram Classified gene: PSMB4 as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.40 PSMB4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for the association of biallelic variants in PSMB4 with lipodystrophy (two unrelated cases and supporting functional evidence). Hence, this gene can be promoted to green rating in the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.40 PSMB4 Achchuthan Shanmugasundram Gene: psmb4 has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.39 PSMB4 Achchuthan Shanmugasundram Tag digenic tag was added to gene: PSMB4.
Tag Q3_23_promote_green tag was added to gene: PSMB4.
Tag Q3_23_NHS_review tag was added to gene: PSMB4.
Severe insulin resistance and lipodystrophy syndromes v4.39 PSMB4 Achchuthan Shanmugasundram Phenotypes for gene: PSMB4 were changed from Proteasome associated autoinflammatory syndrome-1, CANDLES (Chronic, atypical, neutrophillic dermatosis with lipodystrophy and elevated temperature syndrome), Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome) to ?Proteasome-associated autoinflammatory syndrome 3 and digenic forms, OMIM:617591
Severe insulin resistance and lipodystrophy syndromes v4.38 PSMB4 Achchuthan Shanmugasundram Publications for gene: PSMB4 were set to
Severe insulin resistance and lipodystrophy syndromes v4.37 PSMB4 Achchuthan Shanmugasundram edited their review of gene: PSMB4: Added comment: PMID:26524591 - One case with compound heterozygous variants in PSMB4 (monogenic), two cases with heterozygous variants in PSMA3 and PSMB8 (digenic) and two cases with heterozygous variants in PSMB4 and PSMB8 (digenic) were reported with proteasome-associated autoinflammatory syndrome (PRAAS) that includes lipodystrophy and lipid abnormalities. In addition, it was revealed from functional studies that these variants affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity.

PMID:34416217 - A boy with treatment-resistant cutaneous vasculitis was identified with novel heterozygous variants in PSMB4. This patient developed mild lipodystrophy after the successful second hematopoietic stem cell transplantation (HSCT).

This gene has been associated with PRAAS in OMIM and it includes lipodystrophy as one of the clinical manifestations.; Changed rating: GREEN; Changed publications to: 26524591, 34416217
Severe insulin resistance and lipodystrophy syndromes v4.37 PSMB4 Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: These autoinflammatory syndromes include a lipodystrophy (partial and generalised have both been reported) and are caused either by biallelic loss of function mutations (PMID: 26524591, 34416217) or by digenic heterozygous mutations in other proteasome encoding genes (PSMB8, PMSA3 PMID: 26524591). See panel app reviews for autoinflammatory syndromes. PSMB9 has also been implicated in digenic cases but this is in a single familes and lipodystrophy is not reported in the autoinflammatory syndrome of carriers of biallelic loss of function mutations in PSMB9.; to: This gene was added on recommendation of NHSE Genomic Medicine Service:
These autoinflammatory syndromes include a lipodystrophy (partial and generalised have both been reported) and are caused either by biallelic loss of function mutations (PMID: 26524591, 34416217) or by digenic heterozygous mutations in other proteasome encoding genes (PSMB8, PMSA3 PMID: 26524591). See panel app reviews for autoinflammatory syndromes.

PSMB9 has also been implicated in digenic cases but this is in a single familes and lipodystrophy is not reported in the autoinflammatory syndrome of carriers of biallelic loss of function mutations in PSMB9.
Severe insulin resistance and lipodystrophy syndromes v4.37 PSMB8 Achchuthan Shanmugasundram Classified gene: PSMB8 as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.37 PSMB8 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for this gene to be promoted to green rating at the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.37 PSMB8 Achchuthan Shanmugasundram Gene: psmb8 has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.36 PSMB8 Achchuthan Shanmugasundram commented on gene: PSMB8: The 'digenic' tag has been added as there are two cases reported with heterozygous variants from both PSMB4 and PSMB8 in addition to patients with homozygous PSMB8 variants.
Severe insulin resistance and lipodystrophy syndromes v4.36 PSMB8 Achchuthan Shanmugasundram Phenotypes for gene: PSMB8 were changed from Proteasome associated autoinflammatory syndrome-1, CANDLES (Chronic, atypical, neutrophillic dermatosis with lipodystrophy and elevated temperature syndrome), Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome) to Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040
Severe insulin resistance and lipodystrophy syndromes v4.35 PSMB8 Achchuthan Shanmugasundram Publications for gene: PSMB8 were set to
Severe insulin resistance and lipodystrophy syndromes v4.34 PSMB8 Achchuthan Shanmugasundram edited their review of gene: PSMB8: Changed publications to: 20534754, 21129723, 21953331, 26524591
Severe insulin resistance and lipodystrophy syndromes v4.34 PSMB8 Achchuthan Shanmugasundram Tag digenic tag was added to gene: PSMB8.
Tag Q3_23_promote_green tag was added to gene: PSMB8.
Tag Q3_23_NHS_review tag was added to gene: PSMB8.
Severe insulin resistance and lipodystrophy syndromes v4.34 PSMB8 Achchuthan Shanmugasundram edited their review of gene: PSMB8: Added comment: PMID:21129723 - A homozygous missense variant (c.224C>T/ p.Thr75Met) in PSMB8 gene was identified in affected patients from two different families with an autosomal-recessive autoinflammatory syndrome characterised by joint contractures, muscle atrophy, microcytic anaemia, and panniculitis-induced lipodystrophy (JMP).

PMID:21953331 - Of nine patients from eight families reported in this publication with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE syndrome), four patients were homozygous and two were heterozygous for the previously reported missense variant (c.224C>T), one had no PSMB8 variant and one patient was homozygous for a novel nonsense variant (c.405C>A).

This gene has been associated with relevant phenotypes in OMIM (MIM #256040) and Gene2Phenotype ('definitive' rating in the DD panel for Nakajo syndrome) and lipodystrophy has been included as a part of this phenotype in these resources.; Changed rating: GREEN; Changed publications to: 21129723, 21953331
Congenital myopathy v4.30 LETM1 Sarah Leigh Tag Q3_23_NHS_review was removed from gene: LETM1.
Congenital myopathy v4.30 LETM1 Sarah Leigh changed review comment from: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%), myopathy 6/12 (50%) (PMID: 36055214, figure 1c).
Monogenic hearing loss v4.13 LETM1 Sarah Leigh Tag Q3_23_NHS_review was removed from gene: LETM1.
Bilateral congenital or childhood onset cataracts v4.2 LETM1 Sarah Leigh Tag Q3_23_NHS_review was removed from gene: LETM1.
Childhood onset hereditary spastic paraplegia v4.16 LETM1 Sarah Leigh Tag Q3_23_NHS_review was removed from gene: LETM1.
Childhood onset hereditary spastic paraplegia v4.16 LETM1 Sarah Leigh changed review comment from: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%), spasticity 8/15 (53%) (PMID: 36055214, figure 1c).
Paediatric or syndromic cardiomyopathy v3.25 LETM1 Sarah Leigh changed review comment from: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%), cardiomyopathy (5/14, 36%)(PMID: 36055214, figure 1c).
Paediatric or syndromic cardiomyopathy v3.25 LETM1 Sarah Leigh Tag Q3_23_NHS_review was removed from gene: LETM1.
Paediatric or syndromic cardiomyopathy v3.25 LETM1 Sarah Leigh Entity copied from Possible mitochondrial disorder - nuclear genes v3.42
Paediatric or syndromic cardiomyopathy v3.25 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Paediatric or syndromic cardiomyopathy. Sources: Expert Review,Expert Review Amber
Q3_23_promote_green, Q3_23_NHS_review, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Bilateral congenital or childhood onset cataracts v4.2 LETM1 Sarah Leigh Entity copied from Possible mitochondrial disorder - nuclear genes v3.42
Bilateral congenital or childhood onset cataracts v4.2 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Bilateral congenital or childhood onset cataracts. Sources: Expert Review,Expert Review Amber
Q3_23_promote_green, Q3_23_NHS_review, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Monogenic hearing loss v4.13 LETM1 Sarah Leigh Entity copied from Possible mitochondrial disorder - nuclear genes v3.42
Monogenic hearing loss v4.13 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Monogenic hearing loss. Sources: Expert Review,Expert Review Amber
Q3_23_promote_green, Q3_23_NHS_review, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Childhood onset hereditary spastic paraplegia v4.16 LETM1 Sarah Leigh Entity copied from Possible mitochondrial disorder - nuclear genes v3.42
Childhood onset hereditary spastic paraplegia v4.16 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Childhood onset hereditary spastic paraplegia. Sources: Expert Review,Expert Review Amber
Q3_23_promote_green, Q3_23_NHS_review, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Congenital myopathy v4.30 LETM1 Sarah Leigh Entity copied from Possible mitochondrial disorder - nuclear genes v3.42
Congenital myopathy v4.30 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Congenital myopathy. Sources: Expert Review,Expert Review Amber
Q3_23_promote_green, Q3_23_NHS_review, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Likely inborn error of metabolism v4.44 LETM1 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene. PMID: 36055214 reports 12 LETM1 variants in 11 unrelated cases of Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction (OMIM: 620089), together with supportive functional studies.; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).
Mitochondrial disorders v4.71 LETM1 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene. PMID: 36055214 reports 12 LETM1 variants in 11 unrelated cases of Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction (OMIM: 620089), together with supportive functional studies.; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).
Intellectual disability v5.234 LETM1 Sarah Leigh changed review comment from: LETM1 variants has been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).
Early onset or syndromic epilepsy v4.77 LETM1 Sarah Leigh changed review comment from: LETM1 variants has been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).
Possible mitochondrial disorder - nuclear genes v3.42 LETM1 Sarah Leigh changed review comment from: LETM1 variants has been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).
Optic neuropathy v4.10 LETM1 Sarah Leigh changed review comment from: LETM1 variants has been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).
Acute rhabdomyolysis v1.12 SLC22A5 Sarah Leigh Tag Q3_23_MOI was removed from gene: SLC22A5.
Acute rhabdomyolysis v1.12 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v3.24 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v3.23 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.71 SLC22A5 Sarah Leigh Tag Q3_23_MOI was removed from gene: SLC22A5.
Mitochondrial disorders v4.71 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.234 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
DDG2P v3.7 SLC22A5 Sarah Leigh Tag Q3_23_MOI was removed from gene: SLC22A5.
DDG2P v3.7 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v3.100 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.42 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.41 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v4.44 SLC22A5 Sarah Leigh Tag Q3_23_MOI was removed from gene: SLC22A5.
Likely inborn error of metabolism v4.44 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.596 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Short QT syndrome v3.7 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Short QT syndrome v3.6 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v3.7 SLC22A5 Sarah Leigh Tag Q3_23_MOI was removed from gene: SLC22A5.
Rhabdomyolysis and metabolic muscle disorders v3.7 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hyperammonaemia v1.21 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v3.7 SLC22A5 Sarah Leigh changed review comment from: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).; to: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Acute rhabdomyolysis v1.12 SLC22A5 Sarah Leigh changed review comment from: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Paediatric or syndromic cardiomyopathy v3.23 SLC22A5 Sarah Leigh changed review comment from: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Mitochondrial disorders v4.71 SLC22A5 Sarah Leigh changed review comment from: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Intellectual disability v5.233 SLC22A5 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
DDG2P v3.7 SLC22A5 Sarah Leigh changed review comment from: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Fetal anomalies v3.99 SLC22A5 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Possible mitochondrial disorder - nuclear genes v3.41 SLC22A5 Sarah Leigh changed review comment from: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Likely inborn error of metabolism v4.44 SLC22A5 Sarah Leigh changed review comment from: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Undiagnosed metabolic disorders v1.595 SLC22A5 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Short QT syndrome v3.6 SLC22A5 Sarah Leigh changed review comment from: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Rhabdomyolysis and metabolic muscle disorders v3.7 SLC22A5 Sarah Leigh changed review comment from: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Hyperammonaemia v1.20 SLC22A5 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Severe insulin resistance and lipodystrophy syndromes v4.34 PSMB8 Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: These autoinflammatory syndromes include a lipodystrophy (partial and generalised have both been reported) and are caused either by biallelic loss of function mutations (PMID: 20534754, 21129723, 21953331) or by digenic heterozygous mutations in other proteasome encoding genes (PSMB4, PSMA3)(PMID: 26524591). PSMB9 has also been implicated in digenic causes but these are in single kindreds and lipodystrophy is not reported in the autoinflammatory syndrome of carriers of biallelic loss of function mutations in PSMB9.; to: This gene was added on recommendation of NHSE Genomic Medicine Service:
These autoinflammatory syndromes include a lipodystrophy (partial and generalised have both been reported) and are caused either by biallelic loss of function mutations (PMID: 20534754, 21129723, 21953331) or by digenic heterozygous mutations in other proteasome encoding genes (PSMB4, PSMA3)(PMID: 26524591).

PSMB9 has also been implicated in digenic causes but these are in single kindreds and lipodystrophy is not reported in the autoinflammatory syndrome of carriers of biallelic loss of function mutations in PSMB9.
Severe insulin resistance and lipodystrophy syndromes v4.34 EPHX1 Achchuthan Shanmugasundram changed review comment from: Two unrelated cases presenting with lipoatrophic diabetes were identified with de novo variants in EPHX1 gene (patient 1: p.Thr333Pro; patient 2: p.Gly430Arg). The disease was characterised by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analysis showed that these variants protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. In addition, CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response.; to: Two unrelated cases presenting with lipoatrophic diabetes were identified with de novo variants in EPHX1 gene (patient 1: p.Thr333Pro; patient 2: p.Gly430Arg). The disease was characterised by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analysis showed that these variants protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. In addition, CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Severe insulin resistance and lipodystrophy syndromes v4.34 EPHX1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: EPHX1.
Tag Q3_23_NHS_review tag was added to gene: EPHX1.
Severe insulin resistance and lipodystrophy syndromes v4.34 EPHX1 Achchuthan Shanmugasundram Classified gene: EPHX1 as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.34 EPHX1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (two unrelated cases and functional studies) in support of the association of this gene with lipodystrophy and severe insulin resistance. Hence, this gene can be promoted to green rating in the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.34 EPHX1 Achchuthan Shanmugasundram Gene: ephx1 has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.33 EPHX1 Achchuthan Shanmugasundram Phenotypes for gene: EPHX1 were changed from Lipodystrophy, Severe Insulin Resistance to lipodystrophy, MONDO:0006573; Insulin resistance, HP:0000855
Severe insulin resistance and lipodystrophy syndromes v4.32 EPHX1 Achchuthan Shanmugasundram Publications for gene: EPHX1 were set to
Severe insulin resistance and lipodystrophy syndromes v4.31 EPHX1 Achchuthan Shanmugasundram edited their review of gene: EPHX1: Changed rating: GREEN
Severe insulin resistance and lipodystrophy syndromes v4.31 EPHX1 Achchuthan Shanmugasundram edited their review of gene: EPHX1: Added comment: Two unrelated cases presenting with lipoatrophic diabetes were identified with de novo variants in EPHX1 gene (patient 1: p.Thr333Pro; patient 2: p.Gly430Arg). The disease was characterised by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analysis showed that these variants protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. In addition, CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response.; Changed publications to: 34342583
Intellectual disability v5.233 RPS6KA3 Arina Puzriakova Tag Q3_23_MOI tag was added to gene: RPS6KA3.
Intellectual disability v5.233 RPS6KA3 Arina Puzriakova Publications for gene: RPS6KA3 were set to
Intellectual disability v5.232 RPS6KA3 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from XLR to XLD (monoallelic variants in females may cause disease) at the next GMS panel update as several affected female carriers have been reported. ID in female carriers can range from mild to severe which is within the scope of the panel (PMIDs: 12210291; 12030896; 12558110; 17318637). This would also match the current MOI on other GMS panels and OMIM.
Intellectual disability v5.232 RPS6KA3 Arina Puzriakova Mode of inheritance for gene: RPS6KA3 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v3.99 RPS6KA3 Arina Puzriakova Phenotypes for gene: RPS6KA3 were changed from COFFIN-LOWRY SYNDROME to Coffin-Lowry syndrome, OMIM:303600
Adult onset leukodystrophy v3.9 RPS6KA3 Arina Puzriakova Phenotypes for gene: RPS6KA3 were changed from Coffin-Lowry syndrome, 303600 to Coffin-Lowry syndrome, OMIM:303600
Intellectual disability v5.231 RPS6KA3 Arina Puzriakova Phenotypes for gene: RPS6KA3 were changed from Coffin-Lowry syndrome, 303600Mental retardation, X-linked 19, 300844; COFFIN-LOWRY SYNDROME (CLS) to Coffin-Lowry syndrome, OMIM:303600; Intellectual developmental disorder, X-linked 19, OMIM:300844
Severe insulin resistance and lipodystrophy syndromes v4.31 EPHX1 Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: EPHX1 is an epoxide hydroxylase, highly expressed in liver and adipose tissue. De novo missense mutations (p.Thr333Pro and p.Gly430Arg) in EPHX1 carried in heterozygosity were implicated in a lipoatrophic diabetes syndrome in two unrelated probands (PMID: 34342583). In vitro characterisation demonstrated loss of enzyme activity in these two mutants and localisation studies demonstrated aggregation of the mutant EPHX1 isoforms in the ER, suggestive of a dominant negative mechanism of action. Consistent with a causal role for EPHX1 in the affected probands' syndrome, circulating epoxy fatty acids were found to be elevated. Variants implicated in the described clinical syndrome caused EPHX1 to form oligomeric complexes and aggregate in the ER. As such it is likely that simple loss of function mutations in EPHX1 do not cause this syndrome, and a dominant negative effect of the EPHX1 mutants is likely the causal mechanism. Consistent with this EPHX1 appears to be LOF tolerant (pLI gnomad = 0, https://gnomad.broadinstitute.org/gene/ENSG00000143819); to: This gene was added on recommendation of NHSE Genomic Medicine Service:
EPHX1 is an epoxide hydroxylase, highly expressed in liver and adipose tissue. De novo missense mutations (p.Thr333Pro and p.Gly430Arg) in EPHX1 carried in heterozygosity were implicated in a lipoatrophic diabetes syndrome in two unrelated probands (PMID: 34342583). In vitro characterisation demonstrated loss of enzyme activity in these two mutants and localisation studies demonstrated aggregation of the mutant EPHX1 isoforms in the ER, suggestive of a dominant negative mechanism of action. Consistent with a causal role for EPHX1 in the affected probands' syndrome, circulating epoxy fatty acids were found to be elevated. Variants implicated in the described clinical syndrome caused EPHX1 to form oligomeric complexes and aggregate in the ER. As such it is likely that simple loss of function mutations in EPHX1 do not cause this syndrome, and a dominant negative effect of the EPHX1 mutants is likely the causal mechanism. Consistent with this EPHX1 appears to be LOF tolerant (pLI gnomad = 0, https://gnomad.broadinstitute.org/gene/ENSG00000143819).
Severe insulin resistance and lipodystrophy syndromes v4.31 MFN2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: MFN2.
Tag Q3_23_NHS_review tag was added to gene: MFN2.
Severe insulin resistance and lipodystrophy syndromes v4.31 MFN2 Achchuthan Shanmugasundram Classified gene: MFN2 as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.31 MFN2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by NHS, there is sufficient evidence available for associating this gene with lipomatosis and severe insulin resistance and hence this gene can be promoted to green rating at the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.31 MFN2 Achchuthan Shanmugasundram Gene: mfn2 has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.30 MFN2 Achchuthan Shanmugasundram Publications for gene: MFN2 were set to 26085578; 28414270; 3015806
Severe insulin resistance and lipodystrophy syndromes v4.29 MFN2 Achchuthan Shanmugasundram edited their review of gene: MFN2: Changed publications to: 26085578, 28414270, 30158064
Severe insulin resistance and lipodystrophy syndromes v4.29 MFN2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Autosomal recessive variants in this gene have been associated with cephalothoracic lipodystrophy in OMIM (MIM #151800), but not in Gene2Phenotype.
Severe insulin resistance and lipodystrophy syndromes v4.29 MFN2 Achchuthan Shanmugasundram Phenotypes for gene: MFN2 were changed from MFN2-associated multiple lipomatosis, lipodystrophy, severe insulin resistance, axonal sensorimotor neuropathy to Lipomatosis, multiple symmetric, with or without peripheral neuropathy, OMIM:151800
Severe insulin resistance and lipodystrophy syndromes v4.28 MFN2 Achchuthan Shanmugasundram Publications for gene: MFN2 were set to
Severe insulin resistance and lipodystrophy syndromes v4.27 MFN2 Achchuthan Shanmugasundram edited their review of gene: MFN2: Changed rating: GREEN; Changed publications to: 26085578, 28414270, 3015806
Severe insulin resistance and lipodystrophy syndromes v4.27 MFN2 Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: Biallelic R707W mutations or R707W in compound heterozygosity with other loss of function variants cause a complex clinical syndrome consisting of multiple lipomas/upper body adipose tissue overgrowth, concomitant lipoatrophy and the development of severe insulin resistance and its metabolic complications. Affected individuals also have a paucisymptomatic axonal neuropathy. This has now been demonstrated in at least 13 patients from 10 independent families (PMID: 30158064, 28414270, 26085578). It is likely that mitochondrial dysfunction in adipose tissue is crucial to the pathogenesis of this condition but the specific cellular and molecular mechanisms remain to be elucidated.; to: This gene was added on recommendation of NHSE Genomic Medicine Service:
Biallelic R707W mutations or R707W in compound heterozygosity with other loss of function variants cause a complex clinical syndrome consisting of multiple lipomas/upper body adipose tissue overgrowth, concomitant lipoatrophy and the development of severe insulin resistance and its metabolic complications. Affected individuals also have a paucisymptomatic axonal neuropathy. This has now been demonstrated in at least 13 patients from 10 independent families (PMID: 30158064, 28414270, 26085578). It is likely that mitochondrial dysfunction in adipose tissue is crucial to the pathogenesis of this condition but the specific cellular and molecular mechanisms remain to be elucidated.
Severe insulin resistance and lipodystrophy syndromes v4.27 POC1A Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: POC1A.
Tag Q3_23_NHS_review tag was added to gene: POC1A.
Severe insulin resistance and lipodystrophy syndromes v4.27 POC1A Achchuthan Shanmugasundram Classified gene: POC1A as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.27 POC1A Achchuthan Shanmugasundram Added comment: Comment on list classification: As recommended by the NHS, there is sufficient evidence (9 unrelated cases) in support of the association of this gene with severe dyslipidaemic insulin resistance. Hence, this gene can be promoted to green rating at the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.27 POC1A Achchuthan Shanmugasundram Gene: poc1a has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.26 POC1A Achchuthan Shanmugasundram Phenotypes for gene: POC1A were changed from SOFT syndrome, Severe insulin resistance to Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis, OMIM:614813; Insulin resistance, HP:0000855
Severe insulin resistance and lipodystrophy syndromes v4.25 POC1A Achchuthan Shanmugasundram Publications for gene: POC1A were set to
Severe insulin resistance and lipodystrophy syndromes v4.24 POC1A Achchuthan Shanmugasundram edited their review of gene: POC1A: Changed publications to: 22440536, 26336158, 28819016, 33372278, 35234134
Severe insulin resistance and lipodystrophy syndromes v4.24 POC1A Achchuthan Shanmugasundram edited their review of gene: POC1A: Changed rating: GREEN; Changed publications to: 22440536, 26336158, 28819016,33372278, 35234134
Severe insulin resistance and lipodystrophy syndromes v4.24 POC1A Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service:
9 unrelated probands with SHORT syndrome with severe dyslipidaemic insulin resistance are known, this represents 26% of all known cases (PMID: 35234134, 26336158, 28819016, 33372278 ,22440536 see PMID: 35234134 discussion for summary of all published and unpublished cases). Along with ALMS1 and POC1A it is part of a cluster of genes that cause severe insulin resistance syndromes and affect the centrosome/primary cillium though the precise mechanistic basis for the impairment in insulin action is unclear.; to: This gene was added on recommendation of NHSE Genomic Medicine Service:
9 unrelated probands with SHORT syndrome with severe dyslipidaemic insulin resistance are known, this represents 26% of all known cases (PMID: 35234134, 26336158, 28819016, 33372278, 22440536 see PMID: 35234134 discussion for summary of all published and unpublished cases). Along with ALMS1 and POC1A it is part of a cluster of genes that cause severe insulin resistance syndromes and affect the centrosome/primary cillium though the precise mechanistic basis for the impairment in insulin action is unclear.
Severe insulin resistance and lipodystrophy syndromes v4.24 POC1A Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: 9 unrelated probands with SHORT syndrome with severe dyslipidaemic insulin resistance are known, this represents 26% of all known cases (PMID: 35234134, 26336158, 28819016, 33372278 ,22440536 see PMID: 35234134 discussion for summary of all published and unpublished cases). Along with ALMS1 and POC1A it is part of a cluster of genes that cause severe insulin resistance syndromes and affect the centrosome/primary cillium though the precise mechanistic basis for the impairment in insulin action is unclear.; to: This gene was added on recommendation of NHSE Genomic Medicine Service:
9 unrelated probands with SHORT syndrome with severe dyslipidaemic insulin resistance are known, this represents 26% of all known cases (PMID: 35234134, 26336158, 28819016, 33372278 ,22440536 see PMID: 35234134 discussion for summary of all published and unpublished cases). Along with ALMS1 and POC1A it is part of a cluster of genes that cause severe insulin resistance syndromes and affect the centrosome/primary cillium though the precise mechanistic basis for the impairment in insulin action is unclear.
Severe insulin resistance and lipodystrophy syndromes v4.24 CIDEC Achchuthan Shanmugasundram Phenotypes for gene: CIDEC were changed from Lipodystrophy, familial partial, type 5, 615238 to ?Lipodystrophy, familial partial, type 5, OMIM:615238
Severe insulin resistance and lipodystrophy syndromes v4.23 CIDEC Achchuthan Shanmugasundram Classified gene: CIDEC as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.23 CIDEC Achchuthan Shanmugasundram Added comment: Comment on list classification: There is one case with partial lipodystrophy and evidence from mouse models. This gene is already reported in OMIM, but not in Gene2Phenotype. Hence, this gene can only be rated amber with current evidence.
Severe insulin resistance and lipodystrophy syndromes v4.23 CIDEC Achchuthan Shanmugasundram Gene: cidec has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.22 CIDEC Achchuthan Shanmugasundram Publications for gene: CIDEC were set to
Severe insulin resistance and lipodystrophy syndromes v4.21 CIDEC Achchuthan Shanmugasundram edited their review of gene: CIDEC: Changed rating: AMBER; Changed publications to: 20049731, 25565658, 27710244; Changed phenotypes to: ?Lipodystrophy, familial partial, type 5, OMIM:615238
Severe insulin resistance and lipodystrophy syndromes v4.21 PCYT1A Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: Compound heterozygous loss of function mutations co-segregate with lipodystrophy and its metabolic sequelae in two independent pedigrees and PCYT1A knockdown impairs adipogenesis in vitro (PMID: 24889630). These patients did not exhibit features of spondylometaphyseal dysplasia or any retinal disesae, despite dedicated assessment. To our knowledge, the basis for the phenotypic heterogeneity in carriers of biallelic loss of function PCYT1A mutations is not understood.; to: This gene was added on recommendation of NHSE Genomic Medicine Service:
Compound heterozygous loss of function mutations co-segregate with lipodystrophy and its metabolic sequelae in two independent pedigrees and PCYT1A knockdown impairs adipogenesis in vitro (PMID: 24889630). These patients did not exhibit features of spondylometaphyseal dysplasia or any retinal disesae, despite dedicated assessment. To our knowledge, the basis for the phenotypic heterogeneity in carriers of biallelic loss of function PCYT1A mutations is not understood.
Severe insulin resistance and lipodystrophy syndromes v4.21 PCYT1A Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PCYT1A.
Tag Q3_23_NHS_review tag was added to gene: PCYT1A.
Severe insulin resistance and lipodystrophy syndromes v4.21 PCYT1A Achchuthan Shanmugasundram Classified gene: PCYT1A as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.21 PCYT1A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (two unrelated cases and functional studies) for promoting this gene to green rating at the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.21 PCYT1A Achchuthan Shanmugasundram Gene: pcyt1a has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.20 PCYT1A Achchuthan Shanmugasundram edited their review of gene: PCYT1A: Changed rating: GREEN
Severe insulin resistance and lipodystrophy syndromes v4.20 PCYT1A Achchuthan Shanmugasundram Phenotypes for gene: PCYT1A were changed from Spondylometaphyseal dysplasia with cone-rod dystrophy, Congenital lipodystrophy to Spondylometaphyseal dysplasia with cone-rod dystrophy, OMIM:608940; congenital generalized lipodystrophy, MONDO:0006536; Insulin resistance, HP:0000855
Severe insulin resistance and lipodystrophy syndromes v4.19 PCYT1A Achchuthan Shanmugasundram Publications for gene: PCYT1A were set to
Severe insulin resistance and lipodystrophy syndromes v4.18 PCYT1A Achchuthan Shanmugasundram edited their review of gene: PCYT1A: Added comment: Two unrelated patients were identified with biallelic loss-of-function PCYT1A variants (patient 1: p.Glu280del/ p.Val142Met; patient 2: p.Glu280del/ p.333fs) and were reported with lipodystrophy, severe insulin resistance and diabetes. Functional studies showed that the presence of these variants result in near-total lack of PCYT1A expression and significantly reduce PC synthesis via the Kennedy pathway (PMID:24889630). Some of the phenotypes seen in patients such as severe fatty liver and low HDL cholesterol levels have also been seen in the liver-specific deletion of murine PCYT1A gene (PMID:18955728).; Changed publications to: 18955728, 24889630
Severe insulin resistance and lipodystrophy syndromes v4.18 PCNT Achchuthan Shanmugasundram Classified gene: PCNT as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.18 PCNT Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for promoting this gene to green rating at the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.18 PCNT Achchuthan Shanmugasundram Gene: pcnt has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.17 PCNT Achchuthan Shanmugasundram Phenotypes for gene: PCNT were changed from Microcephalic osteodysplastic primordial dwarfism, type II, Severe insulin resistance to Microcephalic osteodysplastic primordial dwarfism, type II, OMIM:210720; Insulin resistance, HP:0000855
Severe insulin resistance and lipodystrophy syndromes v4.16 PCNT Achchuthan Shanmugasundram Publications for gene: PCNT were set to
Severe insulin resistance and lipodystrophy syndromes v4.15 PCNT Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PCNT.
Tag Q3_23_NHS_review tag was added to gene: PCNT.
Severe insulin resistance and lipodystrophy syndromes v4.15 PCNT Achchuthan Shanmugasundram edited their review of gene: PCNT: Added comment: Of 21 patients with biallelic PCNT variants, 18 had insulin resistance, which was severe in the majority of patients. Ten patients had confirmed diabetes (mean age of onset 15 years), and 13 had metabolic dyslipidemia. All patients without insulin resistance were younger than 4 years old. In addition, knockdown of PCNT in adipocytes had no effect on proximal insulin signaling but produced a two-fold impairment in insulin-stimulated glucose uptake, approximately commensurate with an associated defect in cell proliferation and adipogenesis (PMID:21270239).; Changed rating: GREEN; Changed publications to: 21270239
Intellectual disability v5.230 KCNH5 Dmitrijs Rots reviewed gene: KCNH5: 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: PMID: 36307226, 35874597; Phenotypes: Neurodevelopmental disorder and Epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.77 KCNH5 Dmitrijs Rots reviewed gene: KCNH5: 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: PMID: 36307226, 35874597; Phenotypes: NDD with seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare genetic inflammatory skin disorders v3.1 GNB1 Dmitrijs Rots gene: GNB1 was added
gene: GNB1 was added to Rare genetic inflammatory skin disorders. Sources: Literature
Mode of inheritance for gene: GNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNB1 were set to 35119134
Phenotypes for gene: GNB1 were set to Cutaneous mastocytosis; Intellectual developmental disorder, autosomal dominant 42
Mode of pathogenicity for gene: GNB1 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: GNB1 was set to GREEN
Added comment: 5 cases reported with cutaneous mastocytosis and a de novo missense variant (mostly recurrent). Although rare feature (to date reported ~60 cases with GNB1-related disorder), enough evidence for green rating due to mastocytosis.
Sources: Literature
Renal tubulopathies v4.3 RMND1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: RMND1.
Tag Q3_23_NHS_review tag was added to gene: RMND1.
Renal tubulopathies v4.3 RMND1 Achchuthan Shanmugasundram Classified gene: RMND1 as Amber List (moderate evidence)
Renal tubulopathies v4.3 RMND1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating at the next GMS review.
Renal tubulopathies v4.3 RMND1 Achchuthan Shanmugasundram Gene: rmnd1 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v4.2 RMND1 Achchuthan Shanmugasundram Phenotypes for gene: RMND1 were changed from tubulopathy; renal tubular acidosis; interstitial nephritis; end-stage renal disease; tubular atrophy to Combined oxidative phosphorylation deficiency 11, OMIM:614922; tubulopathy; renal tubular acidosis; interstitial nephritis; end-stage renal disease; tubular atrophy
Renal tubulopathies v4.1 RMND1 Achchuthan Shanmugasundram changed review comment from: PMID:31568715 - Four patients identified with pathogenic variants in RMND1 were reported with renal disease characterised by tubulopathy (3/4), renal tubular acidosis (2/4), interstitial nephritis (1/4), and/or end-stage renal disease (4/4) necessitating renal transplantation (2/4).

PMID:31889854 - A very rare homozygous pathogenic variant in RMND1 (p.Val211Met) was identified in a patient presenting with chronic kidney disease (CKD) and sensorineural hearing loss (SNHL).

PMID:32911714 - Compound heterozygous missense variants in RMND1 (p.Gly195Arg & p.Tyr273Ser) was identified in female siblings presenting with severe-to-profound bilateral SNHL, ovarian dysfunction and CKD that developed in the fourth decade of life.; to: PMID:31568715 - Four patients identified with pathogenic variants in RMND1 were reported with renal disease characterised by tubulopathy (3/4), renal tubular acidosis (2/4), interstitial nephritis (1/4), and/or end-stage renal disease (4/4) necessitating renal transplantation (2/4).

PMID:31889854 - A very rare homozygous pathogenic variant in RMND1 (p.Val211Met) was identified in a patient presenting with chronic kidney disease (CKD) and sensorineural hearing loss (SNHL).

PMID:32911714 - Compound heterozygous missense variants in RMND1 (p.Gly195Arg & p.Tyr273Ser) was identified in female siblings presenting with severe-to-profound bilateral SNHL, ovarian dysfunction and CKD that developed in the fourth decade of life.

This gene has been associated with relevant phenotypes in both OMIM (MIM #614922) and Gene2Phenotype. The clinical manifestations such as cystic kidneys, renal tubular acidosis and renal disease have been recorded as part of the OMIM phenotype.
Renal tubulopathies v4.1 RMND1 Achchuthan Shanmugasundram reviewed gene: RMND1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31568715, 31889854, 32911714; Phenotypes: Combined oxidative phosphorylation deficiency 11, OMIM:614922; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.23 MPDZ Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: MPDZ.
Tag Q3_23_NHS_review tag was added to gene: MPDZ.
Retinal disorders v4.23 MPDZ Achchuthan Shanmugasundram Classified gene: MPDZ as Amber List (moderate evidence)
Retinal disorders v4.23 MPDZ Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated cases and supporting functional evidence available for the association of this gene with this panel and hence this gene can be promoted to green rating at the next GMS review.
Retinal disorders v4.23 MPDZ Achchuthan Shanmugasundram Gene: mpdz has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.22 MPDZ Achchuthan Shanmugasundram Phenotypes for gene: MPDZ were changed from to Hydrocephalus, congenital, 2, with or without brain or eye anomalies, OMIM:615219
Retinal disorders v4.21 MPDZ Achchuthan Shanmugasundram Publications for gene: MPDZ were set to PMID 28556411, 36594712, 36429029
Retinal disorders v4.20 MPDZ Achchuthan Shanmugasundram reviewed gene: MPDZ: Rating: GREEN; Mode of pathogenicity: None; Publications: 28556411, 36429029, 36594712; Phenotypes: Hydrocephalus, congenital, 2, with or without brain or eye anomalies, OMIM:615219; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v4.10 HIKESHI Achchuthan Shanmugasundram Tag watchlist was removed from gene: HIKESHI.
Tag Q3_23_promote_green tag was added to gene: HIKESHI.
Tag Q3_23_NHS_review tag was added to gene: HIKESHI.
Optic neuropathy v4.10 HIKESHI Achchuthan Shanmugasundram Classified gene: HIKESHI as Amber List (moderate evidence)
Optic neuropathy v4.10 HIKESHI Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (3 unrelated cases) available now for promoting this gene to green rating at the next GMS review.
Optic neuropathy v4.10 HIKESHI Achchuthan Shanmugasundram Gene: hikeshi has been classified as Amber List (Moderate Evidence).
Optic neuropathy v4.9 HIKESHI Achchuthan Shanmugasundram Publications for gene: HIKESHI were set to 26545878; 28000699
Severe insulin resistance and lipodystrophy syndromes v4.15 PCNT Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: Severe insulin resistance in the absence of frank lipodystrophy is a common feature of Microcephalic osteodysplastic primordial dwarfism, type II due to PCNT mutations (PMID: 21270239). Along with ALMS1 and POC1A it is part of a cluster of genes that cause severe insulin resistance syndromes and affect the centrosome/primary cillium though the precise mechanistic basis for the impairment in insulin action is unclear.; to: This gene was added on recommendation of NHSE Genomic Medicine Service:
Severe insulin resistance in the absence of frank lipodystrophy is a common feature of Microcephalic osteodysplastic primordial dwarfism, type II due to PCNT mutations (PMID: 21270239). Along with ALMS1 and POC1A it is part of a cluster of genes that cause severe insulin resistance syndromes and affect the centrosome/primary cillium though the precise mechanistic basis for the impairment in insulin action is unclear.
Severe insulin resistance and lipodystrophy syndromes v4.15 ALMS1 Achchuthan Shanmugasundram Classified gene: ALMS1 as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.15 ALMS1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available to promote this gene to green rating at the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.15 ALMS1 Achchuthan Shanmugasundram Gene: alms1 has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.14 ALMS1 Achchuthan Shanmugasundram edited their review of gene: ALMS1: Changed phenotypes to: Alstrom syndrome, severe insulin resistance
Severe insulin resistance and lipodystrophy syndromes v4.14 ALMS1 Achchuthan Shanmugasundram Phenotypes for gene: ALMS1 were changed from BIALLELIC, autosomal or pseudoautosomal to Alstrom syndrome, OMIM:203800
Severe insulin resistance and lipodystrophy syndromes v4.13 ALMS1 Achchuthan Shanmugasundram edited their review of gene: ALMS1: Changed phenotypes to: Almstrom syndrome, severe insulin resistance
Severe insulin resistance and lipodystrophy syndromes v4.13 ALMS1 Achchuthan Shanmugasundram Publications for gene: ALMS1 were set to
Severe insulin resistance and lipodystrophy syndromes v4.12 ALMS1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: ALMS1.
Tag Q3_23_NHS_review tag was added to gene: ALMS1.
Severe insulin resistance and lipodystrophy syndromes v4.12 ALMS1 Achchuthan Shanmugasundram edited their review of gene: ALMS1: Added comment: Among 12 unrelated cases with Alstrom syndrome, 10 were identified with ALMS1 variants, of which five had potential founder variant in exon 16. These AS patients had severe early-onset obesity, insulin resistance that increased with age, diabetes, hypertriglyceridemia, and hypertension (PMID:16720663).

Evaluation of 38 patients with AS and matched controls showed that frequent abnormalities include obesity, severe insulin resistance, type 2 diabetes mellitus and adult hypogonadism (PMID:29718281).

This gene has been associated with AS in both OMIM (MIM #203800) and Gene2Phenotype (definitive rating).; Changed rating: GREEN; Changed publications to: 16720663, 29718281, 32958032
Severe insulin resistance and lipodystrophy syndromes v4.12 ALMS1 Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: Severe insulin resistance and its metabolic sequalae are common in Almstrom syndrome (PMID: 32958032, 16720663) which is disproportionate to their adiposity (PMID: 29718281). Along with PCNT and POC1A it is part of a cluster of genes that cause severe insulin resistance syndromes and affect the centrosome/primary cillium though the precise mechanistic basis for the impairment in insulin action is unclear.; to: This gene was added on recommendation of NHSE Genomic Medicine Service:
Severe insulin resistance and its metabolic sequalae are common in Almstrom syndrome (PMID: 32958032, 16720663) which is disproportionate to their adiposity (PMID: 29718281). Along with PCNT and POC1A it is part of a cluster of genes that cause severe insulin resistance syndromes and affect the centrosome/primary cillium though the precise mechanistic basis for the impairment in insulin action is unclear.
Severe insulin resistance and lipodystrophy syndromes v4.12 BLM Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: Expert Review Green (https://panelapp.genomicsengland.co.uk/panels/174/gene/BLM/#!details), partial lipodystrophy and insulin resistance is a recognised clinical feature of bloom syndrome (PMID: 21536711, 29477938, 16763388) and has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244).; to: This gene was added on recommendation of NHSE Genomic Medicine Service:
Expert Review Green (https://panelapp.genomicsengland.co.uk/panels/174/gene/BLM/#!details), partial lipodystrophy and insulin resistance is a recognised clinical feature of bloom syndrome (PMID: 21536711, 29477938, 16763388) and has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244).
Intellectual disability v5.230 LETM1 Sarah Leigh Entity copied from Ataxia and cerebellar anomalies - narrow panel v4.27
Intellectual disability v5.230 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Intellectual disability - microarray and sequencing. Sources: Expert Review Amber,Expert Review
Q3_23_promote_green, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Possible mitochondrial disorder - nuclear genes v3.41 LETM1 Sarah Leigh Tag Q3_23_NHS_review tag was added to gene: LETM1.
Optic neuropathy v4.8 LETM1 Sarah Leigh Entity copied from Possible mitochondrial disorder - nuclear genes v3.41
Optic neuropathy v4.8 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Optic neuropathy. Sources: Expert Review,Expert Review Amber
Q3_23_promote_green, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Ataxia and cerebellar anomalies - narrow panel v4.27 LETM1 Sarah Leigh Entity copied from Possible mitochondrial disorder - nuclear genes v3.41
Ataxia and cerebellar anomalies - narrow panel v4.27 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review,Expert Review Amber
Q3_23_promote_green, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Early onset or syndromic epilepsy v4.77 LETM1 Sarah Leigh Entity copied from Possible mitochondrial disorder - nuclear genes v3.41
Early onset or syndromic epilepsy v4.77 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Early onset or syndromic epilepsy. Sources: Expert Review,Expert Review Amber
Q3_23_promote_green, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Possible mitochondrial disorder - nuclear genes v3.41 LETM1 Sarah Leigh edited their review of gene: LETM1: Added comment: LETM1 variants has been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.41 LETM1 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: LETM1.
Tag Q3_23_MOI tag was added to gene: LETM1.
Possible mitochondrial disorder - nuclear genes v3.41 LETM1 Sarah Leigh Classified gene: LETM1 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.41 LETM1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Possible mitochondrial disorder - nuclear genes v3.41 LETM1 Sarah Leigh Gene: letm1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.71 LETM1 Sarah Leigh Publications for gene: LETM1 were set to 36055214
Laterality disorders and isomerism v3.4 LETM1 Sarah Leigh Publications for gene: LETM1 were set to
Possible mitochondrial disorder - nuclear genes v3.40 LETM1 Sarah Leigh Publications for gene: LETM1 were set to
Severe insulin resistance and lipodystrophy syndromes v4.12 WRN Achchuthan Shanmugasundram Classified gene: WRN as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.12 WRN Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases) in support of the association of this gene to severe insulin resistance/ diabetes and partial lipodystrophy and hence can be promoted to green rating at the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.12 WRN Achchuthan Shanmugasundram Gene: wrn has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.11 WRN Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: WRN.
Tag Q3_23_NHS_review tag was added to gene: WRN.
Severe insulin resistance and lipodystrophy syndromes v4.11 WRN Achchuthan Shanmugasundram Phenotypes for gene: WRN were changed from Werner's Syndrome, partial lipodystrophy, severe insulin resistance to Werner syndrome, OMIM:277700
Severe insulin resistance and lipodystrophy syndromes v4.10 WRN Achchuthan Shanmugasundram Publications for gene: WRN were set to
Severe insulin resistance and lipodystrophy syndromes v4.9 WRN Achchuthan Shanmugasundram edited their review of gene: WRN: Added comment: PMID:22654791 - A homozygous variant (p.Arg732Xaa) in WRN gene has been identified in a 16-year-old female patient with a syndrome comprising short stature, severe insulin resistance, ptosis, and microcephaly.

PMID:23849162 - Biallelic WRN null variants (p.Gln748Xaa homozygous, and compound heterozygous p.Gln1257Xaa/ p.Met1329fs) were identified in two female patients who presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis. One of them also had diabetes.

PMID:35780059 - Compound heterozygous variants (c.1290_1293del/ p.Asn430Lysfs*7 & c.2732+5G>A) in WRN gene was identified in a 28 year-old woman who presented with early onset diabetes associated with partial lipodystrophy, severe dyslipidaemia and rapidly progressive liver fibrosis related to non-alcoholic steatohepatitis in the absence of progeroid features.

This gene has been associated with Werner syndrome in both OMIM (MIM #277700) and Gene2Phenotype.; Changed rating: GREEN; Changed publications to: 22654791, 23849162, 27710244, 35780059
Laterality disorders and isomerism v3.3 LETM1 Sarah Leigh Mode of inheritance for gene: LETM1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Laterality disorders and isomerism v3.2 LETM1 Sarah Leigh Phenotypes for gene: LETM1 were changed from to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Possible mitochondrial disorder - nuclear genes v3.39 LETM1 Sarah Leigh Phenotypes for gene: LETM1 were changed from 620089 Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Severe insulin resistance and lipodystrophy syndromes v4.9 WRN Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: Premature insulin resistant diabetes is widely recognised as a complication of Werner's syndrome and lipoatrophy is commonly reported. Crucially - 3 independent pedigrees have now reported lipodystrophy and/or severe insulin resistance as presenting features of Werner's syndrome highlighting that this condition needs to be considered in the differential diagnosis of lipodystrophy (PMID: 22654791, 35780059, 23849162). It has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244).; to: This gene was added on recommendation of NHSE Genomic Medicine Service:
Premature insulin resistant diabetes is widely recognised as a complication of Werner's syndrome and lipoatrophy is commonly reported. Crucially - 3 independent pedigrees have now reported lipodystrophy and/or severe insulin resistance as presenting features of Werner's syndrome highlighting that this condition needs to be considered in the differential diagnosis of lipodystrophy (PMID: 22654791, 35780059, 23849162). It has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244).
Severe insulin resistance and lipodystrophy syndromes v4.9 AKT2 Achchuthan Shanmugasundram Classified gene: AKT2 as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.9 AKT2 Achchuthan Shanmugasundram Added comment: Comment on list classification: Two unrelated cases and supporting functional evidence from mouse models suggest that this gene can be promoted to green rating in the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.9 AKT2 Achchuthan Shanmugasundram Gene: akt2 has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.8 AKT2 Achchuthan Shanmugasundram Publications for gene: AKT2 were set to 15166380; 17327441
Severe insulin resistance and lipodystrophy syndromes v4.7 AKT2 Achchuthan Shanmugasundram Mode of inheritance for gene: AKT2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe insulin resistance and lipodystrophy syndromes v4.6 AKT2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: AKT2.
Tag Q3_23_NHS_review tag was added to gene: AKT2.
Severe insulin resistance and lipodystrophy syndromes v4.6 AKT2 Achchuthan Shanmugasundram edited their review of gene: AKT2: Added comment: PMID:15166380 - A missense variant (p.Arg274His) in AKT2 gene was identified in a family with autosomal dominant severe insulin resistance, diabetes mellitus and partial lipodystrophy.

PMID:17327441 - Of 94 probands with severe insulin resistance (35 of which had partial lipodystrophy) that were screened for AKT2 variants, one female identified with p.Arg467Trp variant was reported with type 2 diabetes and partial lipodystrophy, while another female identified with p.Arg208Lys variant had severe insulin resistance and acanthosis nigricans. p.Arg467Trp was present in neither 47 ethnically matched control subjects nor in 2 unaffected sons of the carrier. p.Arg208Lys variant was not present in her affected son but was present in 1 of 47 white control subjects.

PMID:12843127 - Functional studies in mice showed that loss of AKT2 results in severe diabetes, age-dependent lipoatrophy and mild growth deficiency.; Changed rating: GREEN; Changed publications to: 12843127, 15166380, 17327441, 27710244
Optic neuropathy v4.7 MCAT Hannah Knight reviewed gene: MCAT: Rating: AMBER; Mode of pathogenicity: None; Publications: 33918393; Phenotypes: Hereditary optic neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v4.7 MCAT Hannah Knight Deleted their review
Optic neuropathy v4.7 MCAT Hannah Knight reviewed gene: MCAT: Rating: AMBER; Mode of pathogenicity: None; Publications: 33918393; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.6 PIK3R1 Achchuthan Shanmugasundram Classified gene: PIK3R1 as Amber List (moderate evidence)
Severe insulin resistance and lipodystrophy syndromes v4.6 PIK3R1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with lipodystrophy and insulin resistance and hence this gene can be promoted to green rating at the next GMS review.
Severe insulin resistance and lipodystrophy syndromes v4.6 PIK3R1 Achchuthan Shanmugasundram Gene: pik3r1 has been classified as Amber List (Moderate Evidence).
Severe insulin resistance and lipodystrophy syndromes v4.5 PIK3R1 Achchuthan Shanmugasundram Phenotypes for gene: PIK3R1 were changed from SHORT syndrome, partial lipodystrophy, severe insulin resistance to SHORT syndrome, OMIM:269880
Severe insulin resistance and lipodystrophy syndromes v4.4 PIK3R1 Achchuthan Shanmugasundram Publications for gene: PIK3R1 were set to
Severe insulin resistance and lipodystrophy syndromes v4.3 PIK3R1 Achchuthan Shanmugasundram Tag Q3_23_NHS_review tag was added to gene: PIK3R1.
Severe insulin resistance and lipodystrophy syndromes v4.3 PIK3R1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PIK3R1.
Severe insulin resistance and lipodystrophy syndromes v4.3 PIK3R1 Achchuthan Shanmugasundram edited their review of gene: PIK3R1: Added comment: PMID:23810378 - Nine affected individuals from eight different families were identified with de novo or inherited PIK3R1 variants, including a mutational hotspot (c.1945C>T/ p.Arg649Trp) present in four families. Insulin resistance was present in seven individuals and lipoatrophy was present in 3 individuals.

PMID:26497935 - Clinical reappraisal of detailed phenotypes of 32 individuals with PIK3R1-associated SHORT syndrome showed that IUGR <= 3rd percentile (19/25), postnatal growth retardation (height < -2SD, 25/31), lipoatrophy (26/29), factual dysmorphism (all 32 cases) and insulin resistance (13/17) are the main features of this disease.

PMID:27766312 - Five patients were reported with SHORT syndrome and C-terminal variants in PIK3R1, of which four had extreme insulin resistance without dyslipidemia or hepatic steatosis.

This gene has been associated with relevant phenotypes in both OMIM (MIM #269880) and Gene2Phenotype ('definitive' rating in the DD panel). Both lipoatrophy (lower face, upper limb, buttock) and insulin resistance diabetes has been associated as clinical manifestations of this OMIM phenotype for SHORT syndrome.; Changed rating: GREEN; Changed publications to: 23810378, 26497935, 27710244, 27766312
Severe insulin resistance and lipodystrophy syndromes v4.3 PIK3R1 Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service. Below are the comments from NHS:
PanelApp expert review green (https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!), Co-segregates with disease in multiple independent pedigrees (PMID: 27766312, 23810378, 26497935), its gene product is a member of the canonical insulin signalling cascade and has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244). SHORT syndrome appears to be caused by C-Terminal mutations affecting the SH2 domain, suggesting a mechanism other than simple loss of function (see Prof Rob Semple's review in Panel app @ https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!); to: This gene was added on recommendation of NHSE Genomic Medicine Service. Below are the comments from NHS:

PanelApp expert review green (https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!), Co-segregates with disease in multiple independent pedigrees (PMID: 27766312, 23810378, 26497935), its gene product is a member of the canonical insulin signalling cascade and has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244).

SHORT syndrome appears to be caused by C-Terminal mutations affecting the SH2 domain, suggesting a mechanism other than simple loss of function (see Prof Rob Semple's review in Panel app @ https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!)
Severe insulin resistance and lipodystrophy syndromes v4.3 PIK3R1 Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service:
PanelApp expert review green (https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!), Co-segregates with disease in multiple independent pedigrees (PMID: 27766312, 23810378, 26497935), its gene product is a member of the canonical insulin signalling cascade and has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244). SHORT syndrome appears to be caused by C-Terminal mutations affecting the SH2 domain, suggesting a mechanism other than simple loss of function (see Prof Rob Semple's review in Panel app @ https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!); to: This gene was added on recommendation of NHSE Genomic Medicine Service. Below are the comments from NHS:
PanelApp expert review green (https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!), Co-segregates with disease in multiple independent pedigrees (PMID: 27766312, 23810378, 26497935), its gene product is a member of the canonical insulin signalling cascade and has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244). SHORT syndrome appears to be caused by C-Terminal mutations affecting the SH2 domain, suggesting a mechanism other than simple loss of function (see Prof Rob Semple's review in Panel app @ https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!)
Severe insulin resistance and lipodystrophy syndromes v4.3 PIK3R1 Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: Panel app expert review green (https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!), Co-segregates with disease in multiple independent pedigrees (PMID: 27766312, 23810378, 26497935), its gene product is a member of the canonical insulin signalling cascade and has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244). SHORT syndrome appears to be caused by C-Terminal mutations affecting the SH2 domain, suggesting a mechanism other than simple loss of function (see Prof Rob Semple's review in Panel app @ https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!); to: This gene was added on recommendation of NHSE Genomic Medicine Service:
PanelApp expert review green (https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!), Co-segregates with disease in multiple independent pedigrees (PMID: 27766312, 23810378, 26497935), its gene product is a member of the canonical insulin signalling cascade and has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244). SHORT syndrome appears to be caused by C-Terminal mutations affecting the SH2 domain, suggesting a mechanism other than simple loss of function (see Prof Rob Semple's review in Panel app @ https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!)
Severe insulin resistance and lipodystrophy syndromes v4.3 CIDEC Achchuthan Shanmugasundram reviewed gene: CIDEC: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Familial Partial Lipodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.3 AKT2 Achchuthan Shanmugasundram reviewed gene: AKT2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Severe insulin resistance, familial partial lipodystrophy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe insulin resistance and lipodystrophy syndromes v4.3 PSMA3 Achchuthan Shanmugasundram reviewed gene: PSMA3: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Proteasome associated autoinflammatory syndrome-1, CANDLES (Chronic, atypical, neutrophillic dermatosis with lipodystrophy and elevated temperature syndrome), Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.3 PSMB4 Achchuthan Shanmugasundram reviewed gene: PSMB4: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Proteasome associated autoinflammatory syndrome-1, CANDLES (Chronic, atypical, neutrophillic dermatosis with lipodystrophy and elevated temperature syndrome), Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.3 PSMB8 Achchuthan Shanmugasundram reviewed gene: PSMB8: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Proteasome associated autoinflammatory syndrome-1, CANDLES (Chronic, atypical, neutrophillic dermatosis with lipodystrophy and elevated temperature syndrome), Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.3 EPHX1 Achchuthan Shanmugasundram reviewed gene: EPHX1: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: Lipodystrophy, Severe Insulin Resistance; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe insulin resistance and lipodystrophy syndromes v4.3 MFN2 Achchuthan Shanmugasundram reviewed gene: MFN2: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: MFN2-associated multiple lipomatosis, lipodystrophy, severe insulin resistance, axonal sensorimotor neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.3 POC1A Achchuthan Shanmugasundram reviewed gene: POC1A: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: SOFT syndrome, Severe insulin resistance; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.3 PCYT1A Achchuthan Shanmugasundram reviewed gene: PCYT1A: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Spondylometaphyseal dysplasia with cone-rod dystrophy, Congenital lipodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.3 PCNT Achchuthan Shanmugasundram reviewed gene: PCNT: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Microcephalic osteodysplastic primordial dwarfism, type II, Severe insulin resistance; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.3 ALMS1 Achchuthan Shanmugasundram reviewed gene: ALMS1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: BIALLELIC, autosomal or pseudoautosomal; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.3 BLM Achchuthan Shanmugasundram reviewed gene: BLM: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Bloom Syndrome, severe insulin resistance; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.3 WRN Achchuthan Shanmugasundram reviewed gene: WRN: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Werner's Syndrome, partial lipodystrophy, severe insulin resistance; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.3 PIK3R1 Achchuthan Shanmugasundram reviewed gene: PIK3R1: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: SHORT syndrome, partial lipodystrophy, severe insulin resistance; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe insulin resistance and lipodystrophy syndromes v4.2 PSMA3 Achchuthan Shanmugasundram gene: PSMA3 was added
gene: PSMA3 was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: PSMA3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PSMA3 were set to Proteasome associated autoinflammatory syndrome-1, CANDLES (Chronic, atypical, neutrophillic dermatosis with lipodystrophy and elevated temperature syndrome), Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome)
Severe insulin resistance and lipodystrophy syndromes v4.2 PSMB4 Achchuthan Shanmugasundram gene: PSMB4 was added
gene: PSMB4 was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: PSMB4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PSMB4 were set to Proteasome associated autoinflammatory syndrome-1, CANDLES (Chronic, atypical, neutrophillic dermatosis with lipodystrophy and elevated temperature syndrome), Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome)
Severe insulin resistance and lipodystrophy syndromes v4.2 PSMB8 Achchuthan Shanmugasundram gene: PSMB8 was added
gene: PSMB8 was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: PSMB8 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PSMB8 were set to Proteasome associated autoinflammatory syndrome-1, CANDLES (Chronic, atypical, neutrophillic dermatosis with lipodystrophy and elevated temperature syndrome), Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome)
Severe insulin resistance and lipodystrophy syndromes v4.2 EPHX1 Achchuthan Shanmugasundram gene: EPHX1 was added
gene: EPHX1 was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: EPHX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EPHX1 were set to Lipodystrophy, Severe Insulin Resistance
Mode of pathogenicity for gene: EPHX1 was set to Other
Severe insulin resistance and lipodystrophy syndromes v4.2 MFN2 Achchuthan Shanmugasundram gene: MFN2 was added
gene: MFN2 was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: MFN2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MFN2 were set to MFN2-associated multiple lipomatosis, lipodystrophy, severe insulin resistance, axonal sensorimotor neuropathy
Mode of pathogenicity for gene: MFN2 was set to Other
Severe insulin resistance and lipodystrophy syndromes v4.2 POC1A Achchuthan Shanmugasundram gene: POC1A was added
gene: POC1A was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: POC1A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: POC1A were set to SOFT syndrome, Severe insulin resistance
Severe insulin resistance and lipodystrophy syndromes v4.2 PCYT1A Achchuthan Shanmugasundram gene: PCYT1A was added
gene: PCYT1A was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: PCYT1A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PCYT1A were set to Spondylometaphyseal dysplasia with cone-rod dystrophy, Congenital lipodystrophy
Severe insulin resistance and lipodystrophy syndromes v4.2 PCNT Achchuthan Shanmugasundram gene: PCNT was added
gene: PCNT was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: PCNT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PCNT were set to Microcephalic osteodysplastic primordial dwarfism, type II, Severe insulin resistance
Severe insulin resistance and lipodystrophy syndromes v4.2 ALMS1 Achchuthan Shanmugasundram gene: ALMS1 was added
gene: ALMS1 was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: ALMS1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ALMS1 were set to BIALLELIC, autosomal or pseudoautosomal
Severe insulin resistance and lipodystrophy syndromes v4.2 BLM Achchuthan Shanmugasundram gene: BLM was added
gene: BLM was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: BLM was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BLM were set to Bloom Syndrome, severe insulin resistance
Severe insulin resistance and lipodystrophy syndromes v4.2 WRN Achchuthan Shanmugasundram gene: WRN was added
gene: WRN was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: WRN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: WRN were set to Werner's Syndrome, partial lipodystrophy, severe insulin resistance
Severe insulin resistance and lipodystrophy syndromes v4.2 PIK3R1 Achchuthan Shanmugasundram gene: PIK3R1 was added
gene: PIK3R1 was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: PIK3R1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PIK3R1 were set to SHORT syndrome, partial lipodystrophy, severe insulin resistance
Mode of pathogenicity for gene: PIK3R1 was set to Other
Insulin resistance (including lipodystrophy) v1.16 PIK3R1 Achchuthan Shanmugasundram Deleted their review
Insulin resistance (including lipodystrophy) v1.16 PIK3R1 Achchuthan Shanmugasundram edited their review of gene: PIK3R1: Changed mode of pathogenicity: Other
Insulin resistance (including lipodystrophy) v1.16 PIK3R1 Achchuthan Shanmugasundram reviewed gene: PIK3R1: Rating: ; 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: ; Phenotypes: ; Mode of inheritance: None
Possible mitochondrial disorder - nuclear genes v3.38 IDH3A Sarah Leigh Tag Q3_23_NHS_review tag was added to gene: IDH3A.
Possible mitochondrial disorder - nuclear genes v3.38 CRLS1 Sarah Leigh Tag Q3_23_NHS_review tag was added to gene: CRLS1.
Possible mitochondrial disorder - nuclear genes v3.38 C2orf69 Sarah Leigh Phenotypes for gene: C2orf69 were changed from Combined oxidative phosphorylation deficiency 53, OMIM:619423 to Combined oxidative phosphorylation deficiency 53, OMIM:619423; combined oxidative phosphorylation deficiency 53, MONDO:0030378
Possible mitochondrial disorder - nuclear genes v3.37 C2orf69 Sarah Leigh Tag Q3_23_NHS_review tag was added to gene: C2orf69.
Mitochondrial disorders v4.70 ATP5O Sarah Leigh Phenotypes for gene: ATP5O were changed from Mitochondrial complex V (ATP synthase) deficiency to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, OMIM:620359
Early onset or syndromic epilepsy v4.76 ATP5O Sarah Leigh Phenotypes for gene: ATP5O were changed from Mitochondrial complex V (ATP synthase) deficiency to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, OMIM:620359
Likely inborn error of metabolism v4.44 ATP5O Sarah Leigh Phenotypes for gene: ATP5O were changed from Mitochondrial complex V (ATP synthase) deficiency to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, OMIM:620359
Fetal anomalies v3.98 ATP5O Sarah Leigh Phenotypes for gene: ATP5O were changed from Mitochondrial complex V (ATP synthase) deficiency to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, OMIM:620359
Mitochondrial disorder with complex V deficiency v2.6 ATP5O Sarah Leigh Phenotypes for gene: ATP5O were changed from Mitochondrial complex V (ATP synthase) deficiency to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, OMIM:620359
Possible mitochondrial disorder - nuclear genes v3.37 ATP5O Sarah Leigh Phenotypes for gene: ATP5O were changed from Mitochondrial complex V (ATP synthase) deficiency to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, OMIM:620359
Possible mitochondrial disorder - nuclear genes v3.36 ATP5O Sarah Leigh Tag Q3_23_NHS_review tag was added to gene: ATP5O.
Intellectual disability v5.229 SLC25A24 Sarah Leigh Publications for gene: SLC25A24 were set to
Structural eye disease v3.4 SLC25A24 Sarah Leigh Publications for gene: SLC25A24 were set to 29100093
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.172 SLC25A24 Sarah Leigh Publications for gene: SLC25A24 were set to 29100094; 29100093
Fetal anomalies v3.97 SLC25A24 Sarah Leigh Publications for gene: SLC25A24 were set to
Pneumothorax - familial v3.3 SLC25A24 Sarah Leigh Publications for gene: SLC25A24 were set to
Pneumothorax - familial v3.2 SLC25A24 Sarah Leigh Phenotypes for gene: SLC25A24 were changed from to Fontaine progeroid syndrome, OMIM; 612289; Fontaine progeroid syndrome, MONDO:0012853
Structural eye disease v3.3 SLC25A24 Sarah Leigh Phenotypes for gene: SLC25A24 were changed from Gorlin-Chaudhry-Moss Syndrome, GCMS; Fontaine progeroid syndrome, 612289 to Fontaine progeroid syndrome, OMIM; 612289; Fontaine progeroid syndrome, MONDO:0012853
Intellectual disability v5.228 SLC25A24 Sarah Leigh Phenotypes for gene: SLC25A24 were changed from to Fontaine progeroid syndrome, OMIM; 612289; Fontaine progeroid syndrome, MONDO:0012853
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.171 SLC25A24 Sarah Leigh Phenotypes for gene: SLC25A24 were changed from Fontaine progeroid syndrome 612289; Gorlin-Chaudhry-Moss to Fontaine progeroid syndrome, OMIM; 612289; Fontaine progeroid syndrome, MONDO:0012853
Fetal anomalies v3.96 SLC25A24 Sarah Leigh Added comment: Comment on phenotypes: Gorlin-Chaudhry-Moss syndrome (GCMS);Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction
Fetal anomalies v3.96 SLC25A24 Sarah Leigh Phenotypes for gene: SLC25A24 were changed from Gorlin-Chaudhry-Moss syndrome (GCMS); Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction to Fontaine progeroid syndrome, OMIM; 612289; Fontaine progeroid syndrome, MONDO:0012853
Mitochondrial disorders v4.69 SLC25A24 Sarah Leigh Tag Q3_23_MOI tag was added to gene: SLC25A24.
Mitochondrial disorders v4.69 SLC25A24 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 2 variants reported in at least nine unrelated cases.; to: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 2 variants reported in at least nine unrelated cases, together with supportive functional studies (PMID: 29100094; 29100093).
Mitochondrial disorders v4.69 SLC25A24 Sarah Leigh edited their review of gene: SLC25A24: Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v4.69 SLC25A24 Sarah Leigh Phenotypes for gene: SLC25A24 were changed from Fontaine progeroid syndrome 612289 to Fontaine progeroid syndrome, OMIM; 612289; Fontaine progeroid syndrome, MONDO:0012853
Mitochondrial disorders v4.68 SLC25A24 Sarah Leigh Classified gene: SLC25A24 as Amber List (moderate evidence)
Mitochondrial disorders v4.68 SLC25A24 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v4.68 SLC25A24 Sarah Leigh Gene: slc25a24 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.67 SLC25A24 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: SLC25A24.
Mitochondrial disorders v4.67 SLC25A20 Sarah Leigh Publications for gene: SLC25A20 were set to 9399886; 31108048; 25778941
Mitochondrial disorders v4.66 SLC25A20 Sarah Leigh Classified gene: SLC25A20 as Amber List (moderate evidence)
Mitochondrial disorders v4.66 SLC25A20 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v4.66 SLC25A20 Sarah Leigh Gene: slc25a20 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.65 SLC25A20 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: SLC25A20.
Mitochondrial disorders v4.65 SLC25A20 Sarah Leigh edited their review of gene: SLC25A20: Added comment: SLC25A20 variants have been associated with Carnitine-acylcarnitine translocase deficiency in OMIM and as definitive Gen2Phen gene for the same condition. Numerous variants have been reported in unrelated cases.; Changed rating: GREEN
Mitochondrial disorders v4.65 SLC25A20 Sarah Leigh Phenotypes for gene: SLC25A20 were changed from Carnitine-acylcarnitine translocase deficiency, 212138 to Carnitine-acylcarnitine translocase deficiency, OMIM:212138; carnitine-acylcarnitine translocase deficiency, MONDO:0008918
Mitochondrial disorders v4.64 SLC25A20 Sarah Leigh Publications for gene: SLC25A20 were set to
Mitochondrial disorders v4.63 SLC22A5 Sarah Leigh Tag Q3_23_MOI tag was added to gene: SLC22A5.
Mitochondrial disorders v4.63 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 9916797; 17884651; 25778941; 28857146
Mitochondrial disorders v4.62 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Added comment: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Short QT syndrome v3.6 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Short QT syndrome v3.5 SLC22A5 Sarah Leigh changed review comment from: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few instances have been reported in cases carrying heterozygous SLC22A5 variants (PMID: 10545605; 11261427).; to: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).
Acute rhabdomyolysis v1.12 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 29895548
Acute rhabdomyolysis v1.11 SLC22A5 Sarah Leigh Tag Q3_23_MOI tag was added to gene: SLC22A5.
Acute rhabdomyolysis v1.11 SLC22A5 Sarah Leigh reviewed gene: SLC22A5: Rating: ; Mode of pathogenicity: None; Publications: 10545605, 11261427; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v5.227 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 9916797; 10425211; 15714519; 10480371; 9700603; 2235122; 20027113; 9634512; 11058897; 3974805; 10051646
Intellectual disability v5.227 SLC22A5 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).
Intellectual disability v5.227 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v3.7 SLC22A5 Sarah Leigh Tag Q3_23_MOI tag was added to gene: SLC22A5.
DDG2P v3.7 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 9916797; 10051646; 2235122; 11058897; 20027113; 9634512; 10425211; 9700603; 15714519; 10480371; 3974805
DDG2P v3.6 SLC22A5 Sarah Leigh reviewed gene: SLC22A5: Rating: ; Mode of pathogenicity: None; Publications: 10545605, 11261427; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v3.95 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to
Fetal anomalies v3.94 SLC22A5 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).
Fetal anomalies v3.94 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.36 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to
Possible mitochondrial disorder - nuclear genes v3.35 SLC22A5 Sarah Leigh reviewed gene: SLC22A5: Rating: ; Mode of pathogenicity: None; Publications: 10545605, 11261427; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.35 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v4.43 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 27604308; 24816252
Likely inborn error of metabolism v4.42 SLC22A5 Sarah Leigh Tag Q3_23_MOI tag was added to gene: SLC22A5.
Likely inborn error of metabolism v4.42 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Added comment: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; Changed rating: GREEN; Changed publications to: 10545605, 11261427; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v3.23 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from DCM; Propionicacidemia; Carnitine transporter deficiency (Disorders of carnitine transport and the carnitine cycle); Arrhythmia, muscle weakness or hypotonia, liver disease, hypoketotic hypoglycaemia; HCM, mixed; Carnitine transporter deficiency (primary carnitine deficiency) to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Short QT syndrome v3.5 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from arrhythmia; short QT; cardiomyopathy; primary carnitine deficiency; Carnitine deficiency, systemic primary 212140 to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Undiagnosed metabolic disorders v1.595 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919 to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Acute rhabdomyolysis v1.11 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from Carnitine deficiency, systemic primary, OMIM:212140 to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Intellectual disability v5.226 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from Carnitine deficiency, systemic primary, 212140 to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Likely inborn error of metabolism v4.42 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from Propionicacidemia; Carnitine transporter deficiency (Disorders of carnitine transport and the carnitine cycle) to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Fetal anomalies v3.93 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from SYSTEMIC PRIMARY CARNITINE DEFICIENCY to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Possible mitochondrial disorder - nuclear genes v3.34 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from Carnitine deficiency, systemic primary, 212140 to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Undiagnosed metabolic disorders v1.594 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from Carnitine transporter deficiency (Disorders of carnitine transport and the carnitine cycle); Propionicacidemia to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Undiagnosed metabolic disorders v1.593 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 27604308; 24816252
Undiagnosed metabolic disorders v1.592 SLC22A5 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).
Undiagnosed metabolic disorders v1.592 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hyperammonaemia v1.20 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from Propionicacidemia 606054 to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Rhabdomyolysis and metabolic muscle disorders v3.7 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from Carnitine deficiency, systemic primary 212140 to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Rhabdomyolysis and metabolic muscle disorders v3.6 SLC22A5 Sarah Leigh Tag Q3_23_MOI tag was added to gene: SLC22A5.
Rhabdomyolysis and metabolic muscle disorders v3.6 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 25929793
Rhabdomyolysis and metabolic muscle disorders v3.5 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Added comment: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; Changed rating: GREEN; Changed publications to: 10545605, 11261427; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hyperammonaemia v1.19 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to
Hyperammonaemia v1.18 SLC22A5 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).
Hyperammonaemia v1.18 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v3.22 SLC22A5 Sarah Leigh Tag Q3_23_MOI was removed from gene: SLC22A5.
Paediatric or syndromic cardiomyopathy v3.22 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Added comment: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; Changed publications to: 10545605, 11261427; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v3.22 SLC22A5 Sarah Leigh Deleted their comment
Short QT syndrome v3.4 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 7254270; 7131143; 26190315; 29198778
Short QT syndrome v3.3 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Added comment: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few instances have been reported in cases carrying heterozygous SLC22A5 variants (PMID: 10545605; 11261427).; Changed publications to: 10545605, 11261427
Short QT syndrome v3.3 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Short QT syndrome v3.3 SLC22A5 Sarah Leigh Deleted their comment
Paediatric or syndromic cardiomyopathy v3.22 SLC22A5 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance should be change from monoallelic to biallelic at the next major review of the panel.
Paediatric or syndromic cardiomyopathy v3.22 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v3.21 SLC22A5 Sarah Leigh Tag Q3_23_MOI tag was added to gene: SLC22A5.
Paediatric or syndromic cardiomyopathy v3.21 SLC22A5 Sarah Leigh reviewed gene: SLC22A5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Short QT syndrome v3.3 SLC22A5 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance is being changed from Monoallelic to Biallelic, as there is no published evidence for monoallelic inheritance of conditions associated with variants in SLC22A5 (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen).
Short QT syndrome v3.3 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v3.21 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 24816252; 27604308
Optic neuropathy v4.7 LHX2 Sarah Leigh edited their review of gene: LHX2: Changed rating: GREEN
Optic neuropathy v4.7 LHX2 Sarah Leigh Classified gene: LHX2 as Amber List (moderate evidence)
Optic neuropathy v4.7 LHX2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Optic neuropathy v4.7 LHX2 Sarah Leigh Gene: lhx2 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v4.6 LHX2 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: LHX2.
Optic neuropathy v4.6 LHX2 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 37057675 reports 17 predominantly de novo LHX2 variants in a panel of patients with a variable neurodevelopmental disorder. Haploinsufficiency and functional studies are supportive of a loss-of-function pathogenic action of the reported LHX2 variants.
Seven out of the ten cases reported in table 1 (PMID: 37057675) are listed as having microcephaly, however, due to lack of clinical information, these cases cannot be classified as severe (personal communication with the author, Christiane Zweier).
Sources: Literature; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 37057675 reports 17 predominantly de novo LHX2 variants in a panel of patients with a variable neurodevelopmental disorder. Haploinsufficiency and functional studies are supportive of a loss-of-function pathogenic action of the reported LHX2 variants.
Nine out of the thirteen cases reported in table 1 (PMID: 37057675) are listed as having Ophthalmologic abnormalities including macular degeneration, optic neuropathy, and esotropia.
Sources: Literature
Optic neuropathy v4.6 LHX2 Sarah Leigh Entity copied from Severe microcephaly v4.28
Optic neuropathy v4.6 LHX2 Sarah Leigh gene: LHX2 was added
gene: LHX2 was added to Optic neuropathy. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: LHX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LHX2 were set to 37057675
Phenotypes for gene: LHX2 were set to neurodevelopmental disorder
Hypogonadotropic hypogonadism (GMS) v3.4 SOX11 Achchuthan Shanmugasundram Classified gene: SOX11 as Amber List (moderate evidence)
Hypogonadotropic hypogonadism (GMS) v3.4 SOX11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>10 unrelated cases) to promote this gene to green rating at the next major update.
Hypogonadotropic hypogonadism (GMS) v3.4 SOX11 Achchuthan Shanmugasundram Gene: sox11 has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v3.3 SOX11 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: SOX11.
Hypogonadotropic hypogonadism (GMS) v3.3 SOX11 Achchuthan Shanmugasundram gene: SOX11 was added
gene: SOX11 was added to Hypogonadotropic hypogonadism (GMS). Sources: Literature
Mode of inheritance for gene: SOX11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOX11 were set to 35341651
Phenotypes for gene: SOX11 were set to Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, OMIM:615866
Review for gene: SOX11 was set to GREEN
Added comment: PMID:35341651 reported 38 unrelated patients with SOX11 variants and idiopathic hypogonadotropic hypogonadism was confirmed as a feature of the intellectual developmental disorder phenotype in eight of these patients. In addition, 3 of 15 cases that were previously reported and reviewed in this publication also had hypogonadotropic hypogonadism.

This gene has been associated with neurodevelopmental disorder phenotypes in both OMIM (MIM #615866) and Gene2Phenotype (with 'definitive' rating in the DD panel) and hypogonadotropic hypogonadism was reported as one of the clinical manifestations in OMIM.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v4.26 AGTPBP1 Achchuthan Shanmugasundram Classified gene: AGTPBP1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.26 AGTPBP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating at the next major update.
Ataxia and cerebellar anomalies - narrow panel v4.26 AGTPBP1 Achchuthan Shanmugasundram Gene: agtpbp1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v4.25 AGTPBP1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: AGTPBP1.
Ataxia and cerebellar anomalies - narrow panel v4.25 AGTPBP1 Achchuthan Shanmugasundram gene: AGTPBP1 was added
gene: AGTPBP1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: AGTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGTPBP1 were set to 30420557
Phenotypes for gene: AGTPBP1 were set to Neurodegeneration, childhood-onset, with cerebellar atrophy, OMIM:618276
Review for gene: AGTPBP1 was set to GREEN
Added comment: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Five unrelated patients had ataxia and all patients had cerebellar atrophy. In addition, functional studies with mouse models have recapitulated the human phenotype.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Sources: Literature
Intellectual disability v5.225 AGTPBP1 Achchuthan Shanmugasundram Classified gene: AGTPBP1 as Amber List (moderate evidence)
Intellectual disability v5.225 AGTPBP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating at the next major update.
Intellectual disability v5.225 AGTPBP1 Achchuthan Shanmugasundram Gene: agtpbp1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.224 AGTPBP1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: AGTPBP1.
Intellectual disability v5.224 AGTPBP1 Achchuthan Shanmugasundram changed review comment from: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe in several patients: Two had severe cognitive delay, one had profound cognitive delay, five had no speech and four had no visual recognition. In addition, functional studies with mouse models have recapitulated the human phenotype.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Sources: Literature; to: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe in several patients: Two had severe cognitive delay, one had profound cognitive delay, five had no speech and four had no visual recognition. In addition, functional studies with mouse models have recapitulated the human phenotype.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Sources: Literature
Intellectual disability v5.224 AGTPBP1 Achchuthan Shanmugasundram changed review comment from: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe, and several patients were unable to speak or have eye contact.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Sources: Literature; to: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe in several patients: Two had severe cognitive delay, one had profound cognitive delay, five had no speech and four had no visual recognition. In addition, functional studies with mouse models have recapitulated the human phenotype.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Sources: Literature
Hereditary neuropathy or pain disorder v3.45 AGTPBP1 Achchuthan Shanmugasundram changed review comment from: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Five unrelated patients had (axonal) motor neuropathy.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).; to: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Five unrelated patients had (axonal) motor neuropathy. In addition, functional studies with mouse models have recapitulated the human phenotype.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Intellectual disability v5.224 AGTPBP1 Achchuthan Shanmugasundram gene: AGTPBP1 was added
gene: AGTPBP1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: AGTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGTPBP1 were set to 30420557
Phenotypes for gene: AGTPBP1 were set to Neurodegeneration, childhood-onset, with cerebellar atrophy, OMIM:618276
Review for gene: AGTPBP1 was set to GREEN
Added comment: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe, and several patients were unable to speak or have eye contact.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Sources: Literature
Adult onset hereditary spastic paraplegia v3.15 Eleanor Williams Panel version 3.14 has been signed off on 2023-07-31
Adult onset neurodegenerative disorder v4.35 Eleanor Williams Panel version 4.34 has been signed off on 2023-07-31
Adult onset dystonia, chorea or related movement disorder v3.13 Eleanor Williams Panel version 3.12 has been signed off on 2023-07-31
Adult onset hereditary spastic paraplegia v3.14 ATXN10_ATTCT Eleanor Williams commented on STR: ATXN10_ATTCT
Adult onset hereditary spastic paraplegia v3.14 ATXN10_ATTCT Eleanor Williams Classified STR: ATXN10_ATTCT as Green List (high evidence)
Adult onset hereditary spastic paraplegia v3.14 ATXN10_ATTCT Eleanor Williams Str: atxn10_attct has been classified as Green List (High Evidence).
Adult onset hereditary spastic paraplegia v3.13 ATXN10_ATTCT Eleanor Williams Tag watchlist was removed from STR: ATXN10_ATTCT.
Tag Q3_23_promote_green was removed from STR: ATXN10_ATTCT.
Adult onset neurodegenerative disorder v4.34 TBP_CAG Eleanor Williams commented on STR: TBP_CAG
Adult onset neurodegenerative disorder v4.34 TBP_CAG Eleanor Williams Classified STR: TBP_CAG as Green List (high evidence)
Adult onset neurodegenerative disorder v4.34 TBP_CAG Eleanor Williams Str: tbp_cag has been classified as Green List (High Evidence).
Adult onset neurodegenerative disorder v4.33 TBP_CAG Eleanor Williams Tag watchlist was removed from STR: TBP_CAG.
Tag Q3_23_promote_green was removed from STR: TBP_CAG.
Adult onset neurodegenerative disorder v4.33 JPH3_CTG Eleanor Williams commented on STR: JPH3_CTG
Adult onset neurodegenerative disorder v4.33 JPH3_CTG Eleanor Williams Classified STR: JPH3_CTG as Green List (high evidence)
Adult onset neurodegenerative disorder v4.33 JPH3_CTG Eleanor Williams Str: jph3_ctg has been classified as Green List (High Evidence).
Adult onset neurodegenerative disorder v4.32 JPH3_CTG Eleanor Williams Tag watchlist was removed from STR: JPH3_CTG.
Tag Q3_23_promote_green was removed from STR: JPH3_CTG.
Adult onset neurodegenerative disorder v4.32 ATN1_CAG Eleanor Williams commented on STR: ATN1_CAG
Adult onset neurodegenerative disorder v4.32 ATN1_CAG Eleanor Williams Classified STR: ATN1_CAG as Green List (high evidence)
Adult onset neurodegenerative disorder v4.32 ATN1_CAG Eleanor Williams Str: atn1_cag has been classified as Green List (High Evidence).
Adult onset neurodegenerative disorder v4.31 ATN1_CAG Eleanor Williams Tag watchlist was removed from STR: ATN1_CAG.
Tag Q3_23_promote_green was removed from STR: ATN1_CAG.
Adult onset dystonia, chorea or related movement disorder v3.12 PPP2R2B_CAG Eleanor Williams commented on STR: PPP2R2B_CAG
Adult onset dystonia, chorea or related movement disorder v3.12 PPP2R2B_CAG Eleanor Williams Classified STR: PPP2R2B_CAG as Green List (high evidence)
Adult onset dystonia, chorea or related movement disorder v3.12 PPP2R2B_CAG Eleanor Williams Str: ppp2r2b_cag has been classified as Green List (High Evidence).
Adult onset dystonia, chorea or related movement disorder v3.11 PPP2R2B_CAG Eleanor Williams Tag watchlist was removed from STR: PPP2R2B_CAG.
Tag Q3_23_promote_green was removed from STR: PPP2R2B_CAG.
Adult onset dystonia, chorea or related movement disorder v3.11 CSTB_CCCCGCCCCGCG Eleanor Williams commented on STR: CSTB_CCCCGCCCCGCG
Adult onset dystonia, chorea or related movement disorder v3.11 CSTB_CCCCGCCCCGCG Eleanor Williams Classified STR: CSTB_CCCCGCCCCGCG as Green List (high evidence)
Adult onset dystonia, chorea or related movement disorder v3.11 CSTB_CCCCGCCCCGCG Eleanor Williams Str: cstb_ccccgccccgcg has been classified as Green List (High Evidence).
Adult onset dystonia, chorea or related movement disorder v3.10 CSTB_CCCCGCCCCGCG Eleanor Williams Tag watchlist was removed from STR: CSTB_CCCCGCCCCGCG.
Tag Q3_23_promote_green was removed from STR: CSTB_CCCCGCCCCGCG.
Adult onset dystonia, chorea or related movement disorder v3.10 CACNA1A_CAG Eleanor Williams commented on STR: CACNA1A_CAG: The rating of this STR has been updated to green after review of STRs on panels that have moved to WGS in phase 2 and NHS Genomic Medicine Service approval.
Adult onset dystonia, chorea or related movement disorder v3.10 CACNA1A_CAG Eleanor Williams Classified STR: CACNA1A_CAG as Green List (high evidence)
Adult onset dystonia, chorea or related movement disorder v3.10 CACNA1A_CAG Eleanor Williams Str: cacna1a_cag has been classified as Green List (High Evidence).
Adult onset dystonia, chorea or related movement disorder v3.9 CACNA1A_CAG Eleanor Williams Tag watchlist was removed from STR: CACNA1A_CAG.
Tag Q3_23_promote_green was removed from STR: CACNA1A_CAG.
Adult onset dystonia, chorea or related movement disorder v3.9 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG: The rating of this STR has been updated to green after review of STRs on panels that have moved to WGS in phase 2 and NHS Genomic Medicine Service approval.
Adult onset dystonia, chorea or related movement disorder v3.9 ATXN3_CAG Eleanor Williams Classified STR: ATXN3_CAG as Green List (high evidence)
Adult onset dystonia, chorea or related movement disorder v3.9 ATXN3_CAG Eleanor Williams Str: atxn3_cag has been classified as Green List (High Evidence).
Adult onset dystonia, chorea or related movement disorder v3.8 ATXN3_CAG Eleanor Williams Tag watchlist was removed from STR: ATXN3_CAG.
Tag Q3_23_promote_green was removed from STR: ATXN3_CAG.
Segmental overgrowth disorders - Deep sequencing v3.7 GJA4 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Tom Cullup (GOSH). There is sufficient evidence to promote this gene to green at the next GMS panel update.

A recurrent GJA4 c.121G>T (p.Gly41Cys) somatic variant has been found in >50 individuals with cavernous venous malformation. The same somatic variant has been found in at least three unrelated cases with cutaneous lesions which plausibly could be referred via this panel. Functional studies have shown this is a GoF variant that leads to formation of a hyperactive hemichannel.; to: Comment on list classification: New gene added by Tom Cullup (GOSH). There is sufficient evidence to promote this gene to green at the next GMS panel update.

A recurrent GJA4 c.121G>T (p.Gly41Cys) somatic variant has been found in >50 individuals with cavernous venous malformation. Functional studies have shown this is a GoF variant that leads to formation of a hyperactive hemichannel.
Adult onset dystonia, chorea or related movement disorder v3.8 ATXN2_CAG Eleanor Williams commented on STR: ATXN2_CAG
Adult onset dystonia, chorea or related movement disorder v3.8 ATXN2_CAG Eleanor Williams Classified STR: ATXN2_CAG as Green List (high evidence)
Adult onset dystonia, chorea or related movement disorder v3.8 ATXN2_CAG Eleanor Williams Str: atxn2_cag has been classified as Green List (High Evidence).
Segmental overgrowth disorders - Deep sequencing v3.7 GJA4 Arina Puzriakova Tag Q3_23_NHS_review was removed from gene: GJA4.
Adult onset dystonia, chorea or related movement disorder v3.7 ATXN2_CAG Eleanor Williams Tag watchlist was removed from STR: ATXN2_CAG.
Tag Q3_23_promote_green was removed from STR: ATXN2_CAG.
Segmental overgrowth disorders - Deep sequencing v3.7 GJA4 Arina Puzriakova Entity copied from Mosaic skin disorders - deep sequencing v2.14
Segmental overgrowth disorders - Deep sequencing v3.7 GJA4 Arina Puzriakova gene: GJA4 was added
gene: GJA4 was added to Segmental overgrowth disorders - Deep sequencing. Sources: Expert Review Amber,Expert list
Q3_23_promote_green, Q3_23_NHS_review, recurrent-variant tags were added to gene: GJA4.
Mode of inheritance for gene: GJA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GJA4 were set to 33912852; 35642047; 35902510; 36209871; 37072338
Phenotypes for gene: GJA4 were set to Cutaneous and hepatic vascular lesions (no OMIM phenotype)
Penetrance for gene: GJA4 were set to unknown
Mode of pathogenicity for gene: GJA4 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mosaic skin disorders - deep sequencing v2.14 GJA4 Arina Puzriakova Publications for gene: GJA4 were set to 33912852
Adult onset dystonia, chorea or related movement disorder v3.7 ATXN1_CAG Eleanor Williams commented on STR: ATXN1_CAG
Adult onset dystonia, chorea or related movement disorder v3.7 ATXN1_CAG Eleanor Williams Classified STR: ATXN1_CAG as Green List (high evidence)
Adult onset dystonia, chorea or related movement disorder v3.7 ATXN1_CAG Eleanor Williams Str: atxn1_cag has been classified as Green List (High Evidence).
Adult onset dystonia, chorea or related movement disorder v3.6 ATXN1_CAG Eleanor Williams Tag watchlist was removed from STR: ATXN1_CAG.
Tag Q3_23_promote_green was removed from STR: ATXN1_CAG.
Mosaic skin disorders - deep sequencing v2.13 GJA4 Arina Puzriakova Classified gene: GJA4 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.13 GJA4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). There is sufficient evidence to promote this gene to green at the next GMS panel update.

A recurrent GJA4 c.121G>T (p.Gly41Cys) somatic variant has been found in >50 individuals with cavernous venous malformation. The same somatic variant has been found in at least three unrelated cases with cutaneous lesions which plausibly could be referred via this panel. Functional studies have shown this is a GoF variant that leads to formation of a hyperactive hemichannel.
Mosaic skin disorders - deep sequencing v2.13 GJA4 Arina Puzriakova Gene: gja4 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v2.12 GJA4 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: GJA4.
Tag Q3_23_NHS_review tag was added to gene: GJA4.
Tag recurrent-variant tag was added to gene: GJA4.
Hereditary neuropathy or pain disorder v3.45 AGTPBP1 Achchuthan Shanmugasundram Classified gene: AGTPBP1 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.45 AGTPBP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating at the next major review.
Hereditary neuropathy or pain disorder v3.45 AGTPBP1 Achchuthan Shanmugasundram Gene: agtpbp1 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.44 AGTPBP1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: AGTPBP1.
Hereditary neuropathy or pain disorder v3.44 AGTPBP1 Achchuthan Shanmugasundram reviewed gene: AGTPBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30420557; Phenotypes: Neurodegeneration, childhood-onset, with cerebellar atrophy, OMIM:618276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.223 ZNF292 Achchuthan Shanmugasundram reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 64, OMIM:619188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.75 PIP5K1C Achchuthan Shanmugasundram Classified gene: PIP5K1C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.75 PIP5K1C Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (seven unrelated cases and supporting functional evidence) for promoting this gene to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.75 PIP5K1C Achchuthan Shanmugasundram Gene: pip5k1c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.74 PIP5K1C Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PIP5K1C.
Early onset or syndromic epilepsy v4.74 PIP5K1C Achchuthan Shanmugasundram Phenotypes for gene: PIP5K1C were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.73 PIP5K1C Achchuthan Shanmugasundram edited their review of gene: PIP5K1C: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
Intellectual disability v5.223 PIP5K1C Achchuthan Shanmugasundram Classified gene: PIP5K1C as Amber List (moderate evidence)
Intellectual disability v5.223 PIP5K1C Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (nine unrelated cases and supporting functional evidence) for promoting this gene to green rating in the next GMS review.
Intellectual disability v5.223 PIP5K1C Achchuthan Shanmugasundram Gene: pip5k1c has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.222 PIP5K1C Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PIP5K1C.
Early onset or syndromic epilepsy v4.73 PIP5K1C Achchuthan Shanmugasundram gene: PIP5K1C was added
gene: PIP5K1C was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: PIP5K1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIP5K1C were set to 37451268
Phenotypes for gene: PIP5K1C were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: PIP5K1C was set to GREEN
Added comment: Three de novo heterozygous missense variants in PIP5K1C (p.Glu146Lys, p.Tyr205Cys & p.Tyr221Cys) were identified in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. Intellectual disability was reported in all nine children and seizures were present in seven children, of which three had developmental and epileptic encephalopathy. In addition, there is functional evidence available, which includes an in vivo zebrafish model that recapitulates the human phenotype (developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities) (PMID:37451268).

This gene has been associated with another phenotype (Lethal congenital contractural syndrome 3, MIM #611369) in both OMIM and Gene2Phenotype, but not yet associated with this neurodevelopmental disorders in either databases.
Sources: Literature
Intellectual disability v5.222 PIP5K1C Achchuthan Shanmugasundram gene: PIP5K1C was added
gene: PIP5K1C was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: PIP5K1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIP5K1C were set to 37451268
Phenotypes for gene: PIP5K1C were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: PIP5K1C was set to GREEN
Added comment: Three de novo heterozygous missense variants in PIP5K1C (p.Glu146Lys, p.Tyr205Cys & p.Tyr221Cys) were identified in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. Intellectual disability was reported in all nine children and seizures were present in seven children, of which three had developmental and epileptic encephalopathy. In addition, there is functional evidence available, which includes an in vivo zebrafish model that recapitulates the human phenotype (developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities) (PMID:37451268).

This gene has been associated with another phenotype (Lethal congenital contractural syndrome 3, MIM #611369) in both OMIM and Gene2Phenotype, but not yet associated with this neurodevelopmental disorders in either databases.
Sources: Literature
Mosaic skin disorders - deep sequencing v2.12 FGFR2 Arina Puzriakova Tag somatic tag was added to gene: FGFR2.
Mosaic skin disorders - deep sequencing v2.12 FGFR2 Arina Puzriakova Publications for gene: FGFR2 were set to 9728990
Mosaic skin disorders - deep sequencing v2.11 FGFR2 Arina Puzriakova Mode of pathogenicity for gene: FGFR2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mosaic skin disorders - deep sequencing v2.10 FGFR2 Arina Puzriakova Classified gene: FGFR2 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.10 FGFR2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to green at the next GMS panel update. FGFR2 is associated with multiple phenotypes but mosaic somatic variants have been found in more than 10 unrelated individuals in literature with nevoid skin disorders.
Mosaic skin disorders - deep sequencing v2.10 FGFR2 Arina Puzriakova Gene: fgfr2 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.33 LETM1 Carl Fratter gene: LETM1 was added
gene: LETM1 was added to Possible mitochondrial disorder - nuclear genes. Sources: Expert Review
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LETM1 were set to 620089 Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction
Review for gene: LETM1 was set to GREEN
Added comment: Consensus opinion from the 3 NHSE GMS specialist mitochondrial providers.
Sources: Expert Review
Mosaic skin disorders - deep sequencing v2.9 FGFR2 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: FGFR2.
Tag Q3_23_NHS_review tag was added to gene: FGFR2.
Paediatric or syndromic cardiomyopathy v3.20 NAA10 Achchuthan Shanmugasundram Classified gene: NAA10 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v3.20 NAA10 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases with paediatric-onset hypertrophic cardiomyopathy. Hence, this gene should be rated amber.
Paediatric or syndromic cardiomyopathy v3.20 NAA10 Achchuthan Shanmugasundram Gene: naa10 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v3.19 NAA10 Achchuthan Shanmugasundram gene: NAA10 was added
gene: NAA10 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: NAA10 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NAA10 were set to 29748569
Phenotypes for gene: NAA10 were set to Ogden syndrome, OMIM:300855
Review for gene: NAA10 was set to AMBER
Added comment: PMID:29748569 reported the identification of previously undescribed NAA10 variant (c.215T>C; p.Ile72Thr) in three boys from two unrelated families with a milder phenotypic spectrum in comparison to most of the previously described patients with NAA10 variants. These boys had developmental delay, intellectual disability, and hypertrophic cardiomyopathy.

This gene has been associated with Ogden syndrome in both OMIM ands Gene2Phenotype and the OMIM record includes hypertrophic cardiomyopathy and other cardiac abnormalities as clinical manifestations of this disorder.
Sources: Literature
Possible mitochondrial disorder - nuclear genes v3.33 IDH3A Carl Fratter edited their review of gene: IDH3A: Added comment: Consensus opinion from the 3 specialist mitochondrial providers.; Changed publications to: 28412069, 28058510, 30478029; Changed phenotypes to: Infantile encephalopathy, 619007 Retinitis pigmentosa 90
Possible mitochondrial disorder - nuclear genes v3.33 CRLS1 Carl Fratter reviewed gene: CRLS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 620167 Combined oxidative phosphorylation deficiency 57; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.33 C2orf69 Carl Fratter reviewed gene: C2orf69: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 619423 Combined oxidative phosphorylation deficiency 53; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.33 ATP5O Carl Fratter edited their review of gene: ATP5O: Added comment: Consensus opinion from the 3 specialist mitochondrial providers.; Changed rating: GREEN; Changed phenotypes to: 620359 Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v3.18 NAA15 Achchuthan Shanmugasundram Publications for gene: NAA15 were set to
Paediatric or syndromic cardiomyopathy v3.17 NAA15 Achchuthan Shanmugasundram Phenotypes for gene: NAA15 were changed from to hypertrophic cardiomyopathy, MONDO:0005045
Paediatric or syndromic cardiomyopathy v3.16 NAA15 Achchuthan Shanmugasundram Mode of inheritance for gene: NAA15 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v3.15 NAA15 Achchuthan Shanmugasundram changed review comment from: PMID:33103328 reported two unrelated individuals with paediatric hypertrophic cardiomyopathy and they were identified with de novo variants in NAA15 gene (patient 1: c.1009_1012delGAAA/ p.Glu337fs, patient 2: c.79A>G/ p.Arg27Gly). These patients presented with cardiomyopathy at 2 months and 6 years of age respectively.

Although none of the patients reported with hypertrophic cardiomyopathy in PMID:29656860, 4 of 19 patients were reported with congenital cardiac defects.

Although this gene has not yet been associated with cardiac abnormalities in OMIM, this gene has been associated with "Congenital heart disease and neurodevelopmental disorder" in the DD panel of Gene2Phenotype database (with 'strong' rating).; to: Comment on gene rating: The rating of this gene should remain amber in this panel, as there are only two unrelated c cases reported with paediatric hypertrophic cardiomyopathy.

PMID:33103328 reported two unrelated individuals with paediatric hypertrophic cardiomyopathy and they were identified with de novo variants in NAA15 gene (patient 1: c.1009_1012delGAAA/ p.Glu337fs, patient 2: c.79A>G/ p.Arg27Gly). These patients presented with cardiomyopathy at 2 months and 6 years of age respectively.

Although none of the patients reported with hypertrophic cardiomyopathy in PMID:29656860, 4 of 19 patients were reported with congenital cardiac defects.

Although this gene has not yet been associated with cardiac abnormalities in OMIM, this gene has been associated with "Congenital heart disease and neurodevelopmental disorder" in the DD panel of Gene2Phenotype database (with 'strong' rating).
Paediatric or syndromic cardiomyopathy v3.15 NAA15 Achchuthan Shanmugasundram reviewed gene: NAA15: Rating: AMBER; Mode of pathogenicity: None; Publications: 33103328; Phenotypes: hypertrophic cardiomyopathy, MONDO:0005045; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v4.20 MPDZ Siying Lin changed review comment from: PMID 28556411: 3 families with affected individuals with biallelic MPDZ variants and congenital hydrocephalus with retinohoroidal coloboma, macular hypoplasia and foveal hypoplasia
PMID 36594712: 2 siblings with biallelic MPDZ variants and macular colobomas
PMID 36429029: proband with biallelic MPDZ variants and macular coloboma
Sources: Literature; to: PMID 28556411: 3 families with affected individuals with biallelic MPDZ variants and congenital hydrocephalus with retinohoroidal coloboma, macular hypoplasia and foveal hypoplasia
PMID 36594712: 2 siblings with biallelic MPDZ variants and macular colobomas
PMID 36429029: proband with biallelic MPDZ variants and macular coloboma
Sources: Literature
Retinal disorders v4.20 MPDZ Siying Lin gene: MPDZ was added
gene: MPDZ was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: MPDZ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPDZ were set to PMID 28556411, 36594712, 36429029
Mode of pathogenicity for gene: MPDZ was set to Other
Added comment: PMID 28556411: 3 families with affected individuals with biallelic MPDZ variants and congenital hydrocephalus with retinohoroidal coloboma, macular hypoplasia and foveal hypoplasia
PMID 36594712: 2 siblings with biallelic MPDZ variants and macular colobomas
PMID 36429029: proband with biallelic MPDZ variants and macular coloboma
Sources: Literature
Early onset or syndromic epilepsy v4.72 TMEM63B Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (17 unrelated cases) in support of promoting this gene to green rating in the next GMS review; to: Comment on list classification: There is sufficient evidence available (17 unrelated cases) in support of promoting this gene to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.72 TMEM63B Achchuthan Shanmugasundram Classified gene: TMEM63B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.72 TMEM63B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (17 unrelated cases) in support of promoting this gene to green rating in the next GMS review
Early onset or syndromic epilepsy v4.72 TMEM63B Achchuthan Shanmugasundram Gene: tmem63b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.71 TMEM63B Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: TMEM63B.
Early onset or syndromic epilepsy v4.71 TMEM63B Achchuthan Shanmugasundram changed review comment from: PMID:37421948 - 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.
Sources: Literature; to: PMID:37421948 - 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%).
Sources: Literature
Intellectual disability v5.221 TMEM63B Achchuthan Shanmugasundram Classified gene: TMEM63B as Amber List (moderate evidence)
Intellectual disability v5.221 TMEM63B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (17 unrelated cases) in support of promoting this gene to green rating in the next GMS review.
Intellectual disability v5.221 TMEM63B Achchuthan Shanmugasundram Gene: tmem63b has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.220 TMEM63B Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: TMEM63B.
Early onset or syndromic epilepsy v4.71 TMEM63B Achchuthan Shanmugasundram gene: TMEM63B was added
gene: TMEM63B was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: TMEM63B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM63B were set to 37421948
Phenotypes for gene: TMEM63B were set to developmental and epileptic encephalopathy, MONDO:0100062
Review for gene: TMEM63B was set to GREEN
Added comment: PMID:37421948 - 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.
Sources: Literature
Intellectual disability v5.220 TMEM63B Achchuthan Shanmugasundram gene: TMEM63B was added
gene: TMEM63B was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: TMEM63B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM63B were set to 37421948
Phenotypes for gene: TMEM63B were set to developmental and epileptic encephalopathy, MONDO:0100062
Review for gene: TMEM63B was set to GREEN
Added comment: PMID:37421948 - 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.
Sources: Literature
Intellectual disability v5.219 DHX9 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.219 DHX9 Achchuthan Shanmugasundram Classified gene: DHX9 as Amber List (moderate evidence)
Intellectual disability v5.219 DHX9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (eight unrelated cases) in support of promoting this gene to green rating at the next GMS review.
Intellectual disability v5.219 DHX9 Achchuthan Shanmugasundram Gene: dhx9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.219 DHX9 Achchuthan Shanmugasundram Classified gene: DHX9 as Amber List (moderate evidence)
Intellectual disability v5.219 DHX9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (eight unrelated cases) in support of promoting this gene to green rating at the next GMS review.
Intellectual disability v5.219 DHX9 Achchuthan Shanmugasundram Gene: dhx9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.218 DHX9 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: DHX9.
Intellectual disability v5.218 DHX9 Achchuthan Shanmugasundram gene: DHX9 was added
gene: DHX9 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: DHX9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX9 were set to 37467750
Phenotypes for gene: DHX9 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: DHX9 was set to GREEN
Added comment: PMID:37467750 - 17 unrelated individuals were identified with de novo, ultra-rare, heterozygous missense or loss-of-function DHX9 variants, of which 14 individuals were reported with a neurodevelopmental disorder (NDD) and three were reported with Charcot-Marie-Tooth disease (CMT). All 14 cases with NDD had developmental delay, of which eight were reported with intellectual disability (4 severe, 1 moderate, 3 mild). Two cases did not have ID, one had borderline ID and three cases were too young (0-5 years old).
Sources: Literature
Hereditary neuropathy or pain disorder v3.44 DHX9 Achchuthan Shanmugasundram Classified gene: DHX9 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.44 DHX9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases) for promoting this gene to green rating in the next major update.
Hereditary neuropathy or pain disorder v3.44 DHX9 Achchuthan Shanmugasundram Gene: dhx9 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.43 DHX9 Achchuthan Shanmugasundram Tag watchlist was removed from gene: DHX9.
Tag Q3_23_promote_green tag was added to gene: DHX9.
Hereditary neuropathy or pain disorder v3.43 DHX9 Achchuthan Shanmugasundram Phenotypes for gene: DHX9 were changed from Adult-onset axonal neuropathy to Adult-onset axonal neuropathy; Charcot-Marie-Tooth disease, MONDO:0015626
Hereditary neuropathy or pain disorder v3.42 DHX9 Achchuthan Shanmugasundram Publications for gene: DHX9 were set to
Hereditary neuropathy or pain disorder v3.41 DHX9 Achchuthan Shanmugasundram Mode of inheritance for gene: DHX9 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.40 DHX9 Achchuthan Shanmugasundram reviewed gene: DHX9: Rating: GREEN; Mode of pathogenicity: None; Publications: 37467750; Phenotypes: Charcot-Marie-Tooth disease, MONDO:0015626; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - narrow panel v4.24 DNAJC3 Achchuthan Shanmugasundram Classified gene: DNAJC3 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.24 DNAJC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated families identified with biallelic DNAJC3 variants and reported with gait ataxia since childhood/ adolescence. Hence, this gene can be promoted to Green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v4.24 DNAJC3 Achchuthan Shanmugasundram Gene: dnajc3 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v4.23 DNAJC3 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: DNAJC3.
Ataxia and cerebellar anomalies - narrow panel v4.23 DNAJC3 Achchuthan Shanmugasundram gene: DNAJC3 was added
gene: DNAJC3 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: DNAJC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC3 were set to 25466870; 28940199; 32738013; 33486469; 34654017
Phenotypes for gene: DNAJC3 were set to Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus, OMIM:616192
Review for gene: DNAJC3 was set to GREEN
Added comment: PMID:25466870 - Five individuals from two different families were identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)) and reported with gait ataxia as one of the clinical manifestations. The onset of gait disturbances was during childhood/ adolescence for four of these cases.

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with gait ataxia since 15 years of age.

PMID:32738013 - Two unrelated children were identified with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with gait ataxia.

PMID:33486469 - Two unrelated patients were identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (patient 2: p.Arg393Ter) variants, of which patient 1 had ataxia.

PMID:34654017 - Two siblings (aged 10 and 5 years) identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with gait ataxia.
Sources: Literature
Hereditary neuropathy v1.472 DNAJC3 Achchuthan Shanmugasundram changed review comment from: PMID:25466870 - Five individuals from two different families with demyelinating sensorimotor peripheral neuropathy and identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)).

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with demyelinating sensorimotor peripheral neuropathy.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorimotor demyelinating and axonal polyneuropathy among several clinical manifestations.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, of which patient 1 had demyelinating peripheral sensorimotor neuropathy.

PMID:34654017 - One of two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with demyelinating neuropathy among several other clinical manifestations.; to: PMID:25466870 - Five individuals from two different families with demyelinating sensorimotor peripheral neuropathy and identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)).

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with demyelinating sensorimotor peripheral neuropathy.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorimotor demyelinating and axonal polyneuropathy.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, of which patient 1 had demyelinating peripheral sensorimotor neuropathy.

PMID:34654017 - One of two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with demyelinating neuropathy.
Monogenic hearing loss v4.12 DNAJC3 Achchuthan Shanmugasundram Classified gene: DNAJC3 as Amber List (moderate evidence)
Monogenic hearing loss v4.12 DNAJC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are seven unrelated families with DNAJC3 biallelic variants and presenting with sensorineural hearing loss. Hence, this gene can be promoted to Green at the next GMS review.
Monogenic hearing loss v4.12 DNAJC3 Achchuthan Shanmugasundram Gene: dnajc3 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v4.11 DNAJC3 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: DNAJC3.
Monogenic hearing loss v4.11 DNAJC3 Achchuthan Shanmugasundram changed review comment from: PMID:25466870 - Five individuals from two different families were identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)), of which all three individuals from family 1 and one of two individuals from family 2 were reported with sensorineural hearing loss among several clinical manifestations.

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with sensorineural hearing loss.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorineural hearing loss.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, and both had sensorineural hearing loss.

PMID:34654017 - Ttwo siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with sensorineural hearing loss.
Sources: Literature; to: PMID:25466870 - Five individuals from two different families were identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)), of which all three individuals from family 1 and one of two individuals from family 2 were reported with sensorineural hearing loss among several clinical manifestations.

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with sensorineural hearing loss.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorineural hearing loss.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, and both had sensorineural hearing loss.

PMID:34654017 - Two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with sensorineural hearing loss.
Sources: Literature
Monogenic hearing loss v4.11 DNAJC3 Achchuthan Shanmugasundram gene: DNAJC3 was added
gene: DNAJC3 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: DNAJC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC3 were set to 25466870; 28940199; 32738013; 33486469; 34654017
Phenotypes for gene: DNAJC3 were set to Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus, OMIM:616192
Review for gene: DNAJC3 was set to GREEN
Added comment: PMID:25466870 - Five individuals from two different families were identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)), of which all three individuals from family 1 and one of two individuals from family 2 were reported with sensorineural hearing loss among several clinical manifestations.

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with sensorineural hearing loss.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorineural hearing loss.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, and both had sensorineural hearing loss.

PMID:34654017 - Ttwo siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with sensorineural hearing loss.
Sources: Literature
Hereditary neuropathy or pain disorder v3.40 DNAJC3 Achchuthan Shanmugasundram changed review comment from: PMID:25466870 - Five individuals from two different families with demyelinating sensorimotor peripheral neuropathy and identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)).

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with demyelinating sensorimotor peripheral neuropathy.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorimotor demyelinating and axonal polyneuropathy.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, of which patient 1 had demyelinating peripheral sensorimotor neuropathy.

PMID:34654017 - One of two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with demyelinating neuropathy among several other clinical manifestations.; to: PMID:25466870 - Five individuals from two different families with demyelinating sensorimotor peripheral neuropathy and identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)).

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with demyelinating sensorimotor peripheral neuropathy.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorimotor demyelinating and axonal polyneuropathy.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, of which patient 1 had demyelinating peripheral sensorimotor neuropathy.

PMID:34654017 - One of two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with demyelinating neuropathy.
Hereditary neuropathy or pain disorder v3.40 DNAJC3 Achchuthan Shanmugasundram changed review comment from: PMID:25466870 - Five individuals from two different families with demyelinating sensorimotor peripheral neuropathy and identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)).

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with demyelinating sensorimotor peripheral neuropathy.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorimotor demyelinating and axonal polyneuropathy among several clinical manifestations.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, of which patient 1 had demyelinating peripheral sensorimotor neuropathy.

PMID:34654017 - One of two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with demyelinating neuropathy among several other clinical manifestations.; to: PMID:25466870 - Five individuals from two different families with demyelinating sensorimotor peripheral neuropathy and identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)).

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with demyelinating sensorimotor peripheral neuropathy.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorimotor demyelinating and axonal polyneuropathy.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, of which patient 1 had demyelinating peripheral sensorimotor neuropathy.

PMID:34654017 - One of two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with demyelinating neuropathy among several other clinical manifestations.
Hereditary neuropathy v1.472 DNAJC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence (six unrelated families) available for promoting this gene to green rating.; to: Comment on list classification: There is sufficient evidence (six unrelated families) available for promoting this gene to green rating in this panel.
Hereditary neuropathy v1.472 DNAJC3 Achchuthan Shanmugasundram Classified gene: DNAJC3 as Green List (high evidence)
Hereditary neuropathy v1.472 DNAJC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (six unrelated families) available for promoting this gene to green rating.
Hereditary neuropathy v1.472 DNAJC3 Achchuthan Shanmugasundram Gene: dnajc3 has been classified as Green List (High Evidence).
Hereditary neuropathy v1.471 DNAJC3 Achchuthan Shanmugasundram Publications for gene: DNAJC3 were set to 25466870
Hereditary neuropathy v1.470 DNAJC3 Achchuthan Shanmugasundram reviewed gene: DNAJC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25466870, 28940199, 32738013, 33486469, 34654017; Phenotypes: Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus, OMIM:616192; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.40 DNAJC3 Achchuthan Shanmugasundram edited their review of gene: DNAJC3: Changed publications to: 25466870, 28940199, 32738013, 33486469, 34654017
Hereditary neuropathy or pain disorder v3.40 DNAJC3 Achchuthan Shanmugasundram Publications for gene: DNAJC3 were set to 25466870; 28940199; 32738013; 3348646934654017
Hereditary neuropathy or pain disorder v3.39 DNAJC3 Achchuthan Shanmugasundram Classified gene: DNAJC3 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.39 DNAJC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with DNAJC3 biallelic variants and presenting with demyelinating sensorimotor peripheral neuropathy. Hence, this gene can be promoted to Green at the next GMS review.
Hereditary neuropathy or pain disorder v3.39 DNAJC3 Achchuthan Shanmugasundram Gene: dnajc3 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.38 DNAJC3 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: DNAJC3.
Hereditary neuropathy or pain disorder v3.38 DNAJC3 Achchuthan Shanmugasundram Publications for gene: DNAJC3 were set to 25466870
Hereditary neuropathy or pain disorder v3.37 DNAJC3 Achchuthan Shanmugasundram reviewed gene: DNAJC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25466870, 28940199, 32738013, 3348646934654017; Phenotypes: Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus, OMIM:616192; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v4.5 HIKESHI Hannah Knight reviewed gene: HIKESHI: Rating: GREEN; Mode of pathogenicity: None; Publications: 34111619; Phenotypes: Leukodystrophy, hypomyelinating; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.20 DYNC2H1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: DYNC2H1.
Retinal disorders v4.20 DYNC2H1 Achchuthan Shanmugasundram Classified gene: DYNC2H1 as Amber List (moderate evidence)
Retinal disorders v4.20 DYNC2H1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (five unrelated cases) in support of the association of this gene with inherited retinal disease. Hence, this gene can be promoted to green rating in the next GMS review.
Retinal disorders v4.20 DYNC2H1 Achchuthan Shanmugasundram Gene: dync2h1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.19 DYNC2H1 Achchuthan Shanmugasundram Phenotypes for gene: DYNC2H1 were changed from to retinitis pigmentosa, MONDO:0019200
Retinal disorders v4.18 DYNC2H1 Achchuthan Shanmugasundram Publications for gene: DYNC2H1 were set to
Retinal disorders v4.17 DYNC2H1 Achchuthan Shanmugasundram reviewed gene: DYNC2H1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32753734; Phenotypes: retinitis pigmentosa, MONDO:0019200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset dystonia, chorea or related movement disorder v3.6 UCHL1 Sarah Leigh Mode of inheritance for gene: UCHL1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.22 UCHL1 Sarah Leigh Tag Q3_23_MOI tag was added to gene: UCHL1.
Ataxia and cerebellar anomalies - narrow panel v4.22 UCHL1 Sarah Leigh commented on gene: UCHL1: Childhood onset cerebellar ataxia and has been reported in both Spastic paraplegia 79A, autosomal dominant, OMIM:620221 and Spastic paraplegia 79B, autosomal recessive, OMIM:615491, therefore, the mode of inheritance for this gene should be: BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v4.22 UCHL1 Sarah Leigh edited their review of gene: UCHL1: Changed rating: GREEN
Adult onset dystonia, chorea or related movement disorder v3.5 UCHL1 Sarah Leigh changed review comment from: In addition to previous reports of Spastic paraplegia 79, autosomal recessive (OMIM:615491), PMID: 35986737 reports a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy in cases with heterozygous UCHL1 variants. The variants included 13 heterozygous loss-of-function variants (15 families) and a heterozygous in-frame insertion (3 families). The affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17), it was also noted in PMID: 35986737 that the condition onset in dominant cases was median 49 years (12-70 years) and in recessive was 7.5 years (2-10 years).; to: In addition to previous reports of Spastic paraplegia 79, autosomal recessive (OMIM:615491), PMID: 35986737 reports a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy in cases with heterozygous UCHL1 variants. The variants included 13 heterozygous loss-of-function variants (15 families) and a heterozygous in-frame insertion (3 families). The affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17), it was also noted in PMID: 35986737 that the condition onset in dominant cases was median 49 years (12-70 years) and in recessive was 7.5 years (2-10 years). However, dystonia was only reported in one case in this study (Table 5S).
Hereditary ataxia with onset in adulthood v4.17 UCHL1 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: UCHL1.
Tag Q3_23_MOI tag was added to gene: UCHL1.
Adult onset hereditary spastic paraplegia v3.13 UCHL1 Sarah Leigh Classified gene: UCHL1 as Amber List (moderate evidence)
Adult onset hereditary spastic paraplegia v3.13 UCHL1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Adult onset hereditary spastic paraplegia v3.13 UCHL1 Sarah Leigh Gene: uchl1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v4.17 UCHL1 Sarah Leigh Classified gene: UCHL1 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v4.17 UCHL1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary ataxia with onset in adulthood v4.17 UCHL1 Sarah Leigh Gene: uchl1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v4.16 UCHL1 Sarah Leigh edited their review of gene: UCHL1: Changed rating: GREEN
Hereditary ataxia with onset in adulthood v4.16 UCHL1 Sarah Leigh changed review comment from: In addition to previous reports of Spastic paraplegia 79, autosomal recessive (OMIM:615491), PMID: 35986737 reports a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy in cases with heterozygous UCHL1 variants. The variants included 13 heterozygous loss-of-function variants (15 families) and a heterozygous in-frame insertion (3 families). The affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17), it was also noted in PMID: 35986737 that the condition onset in dominant cases was median 49 years (12-70 years) and in recessive was 7.5 years (2-10 years).; to: In addition to previous reports of Spastic paraplegia 79, autosomal recessive (OMIM:615491), PMID: 35986737 reports a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy in cases with heterozygous UCHL1 variants. The variants included 13 heterozygous loss-of-function variants (15 families) and a heterozygous in-frame insertion (3 families). The affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17), it was also noted in PMID: 35986737 that the condition onset in dominant cases was median 49 years (12-70 years) and in recessive was 7.5 years (2-10 years).
Adult onset hereditary spastic paraplegia v3.12 UCHL1 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: UCHL1.
Tag Q3_23_MOI tag was added to gene: UCHL1.
Adult onset hereditary spastic paraplegia v3.12 UCHL1 Sarah Leigh edited their review of gene: UCHL1: Added comment: Spasticity was reported in at least six families carrying heterozygous UCHL1 variants (PMID: 35986737, figure 2 & table S5). Overall, the disease onset for Spastic paraplegia 79A, autosomal dominant, OMIM:620221 had a median of 49 years (12-70years).; Changed rating: GREEN; Changed publications to: 35986737
Childhood onset hereditary spastic paraplegia v4.15 UCHL1 Sarah Leigh Tag Q3_23_MOI tag was added to gene: UCHL1.
Childhood onset hereditary spastic paraplegia v4.15 UCHL1 Sarah Leigh reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359680, 28007905, 35986737; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v4.5 UCHL1 Sarah Leigh Tag Q3_23_MOI tag was added to gene: UCHL1.
Optic neuropathy v4.5 UCHL1 Sarah Leigh reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359680, 28007905, 35986737; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.331 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491 to Spastic paraplegia 79B, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Ataxia and cerebellar anomalies - narrow panel v4.22 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209 to Spastic paraplegia 79B, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Adult onset dystonia, chorea or related movement disorder v3.5 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; ?{Parkinson disease 5, susceptibility to}, OMIM:613643; Parkinson disease 5, autosomal dominant, susceptibility to' MONDO:0013340 to {?Parkinson disease 5, susceptibility to}, OMIM:613643; Parkinson disease 5, autosomal dominant, susceptibility to, MONDO:0013340; Spastic paraplegia 79B, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Hereditary ataxia with onset in adulthood v4.16 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209 to Spastic paraplegia 79B, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Adult onset neurodegenerative disorder v4.31 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from {?Parkinson disease 5, susceptibility to}, OMIM:613643; Parkinson disease 5, autosomal dominant, susceptibility to, MONDO:0013340; Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221 to {?Parkinson disease 5, susceptibility to}, OMIM:613643; Parkinson disease 5, autosomal dominant, susceptibility to, MONDO:0013340; Spastic paraplegia 79B, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Adult onset hereditary spastic paraplegia v3.12 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221 to Spastic paraplegia 79B, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Childhood onset hereditary spastic paraplegia v4.15 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221 to Spastic paraplegia 79B, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Optic neuropathy v4.5 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221 to Spastic paraplegia 79B, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Adult onset neurodegenerative disorder v4.30 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from ?{Parkinson disease 5, susceptibility to}; Early onset ataxia and optic neuropathy to {?Parkinson disease 5, susceptibility to}, OMIM:613643; Parkinson disease 5, autosomal dominant, susceptibility to, MONDO:0013340; Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Adult onset hereditary spastic paraplegia v3.11 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209 to Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Childhood onset hereditary spastic paraplegia v4.14 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491 to Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Childhood onset hereditary spastic paraplegia v4.13 AMFR Achchuthan Shanmugasundram changed review comment from: PMID:37119330 - 20 individuals from 8 unrelated consanguineous families of various origins were identified with autosomal recessive variants in AMFR gene. All patients had early disease onset (<3 years), including motor delay, lower limb hyperreflexia and spastic paraplegia that match the typical phenotypes of hereditary spastic paraplegia.
Sources: Literature; to: PMID:37119330 - 20 individuals from 8 unrelated consanguineous families of various origins were identified with autosomal recessive variants in AMFR gene. All patients had early disease onset (<3 years), including motor delay, lower limb hyperreflexia and spastic paraplegia that match the typical phenotypes of hereditary spastic paraplegia.

This gene has been associated with relevant phenotypes in OMIM (MIM #620379), but not in Gene2Phenotype.
Sources: Literature
Optic neuropathy v4.4 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, 615491 to Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Childhood onset hereditary spastic paraplegia v4.13 AMFR Achchuthan Shanmugasundram Classified gene: AMFR as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v4.13 AMFR Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating at the next GMS review.
Childhood onset hereditary spastic paraplegia v4.13 AMFR Achchuthan Shanmugasundram Gene: amfr has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v4.12 AMFR Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: AMFR.
Childhood onset hereditary spastic paraplegia v4.12 AMFR Achchuthan Shanmugasundram gene: AMFR was added
gene: AMFR was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: AMFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMFR were set to 37119330
Phenotypes for gene: AMFR were set to Spastic paraplegia 89, autosomal recessive, OMIM:620379
Review for gene: AMFR was set to GREEN
Added comment: PMID:37119330 - 20 individuals from 8 unrelated consanguineous families of various origins were identified with autosomal recessive variants in AMFR gene. All patients had early disease onset (<3 years), including motor delay, lower limb hyperreflexia and spastic paraplegia that match the typical phenotypes of hereditary spastic paraplegia.
Sources: Literature
Adult onset neurodegenerative disorder v4.29 UCHL1 Sarah Leigh Publications for gene: UCHL1 were set to PMID: 23359680
Childhood onset hereditary spastic paraplegia v4.11 UCHL1 Sarah Leigh Publications for gene: UCHL1 were set to 23359680; 28007905; 29735986; 32656641; 11555633; 33159930
Optic neuropathy v4.3 UCHL1 Sarah Leigh Publications for gene: UCHL1 were set to 29735986; 23359680; 28007905
Early onset or syndromic epilepsy v4.70 CNOT9 Achchuthan Shanmugasundram Classified gene: CNOT9 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.70 CNOT9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (five unrelated cases) for this gene to be promoted to Green at the next major update.
Early onset or syndromic epilepsy v4.70 CNOT9 Achchuthan Shanmugasundram Gene: cnot9 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.69 CNOT9 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: CNOT9.
Early onset or syndromic epilepsy v4.69 CNOT9 Achchuthan Shanmugasundram Phenotypes for gene: CNOT9 were changed from epilepsy, MONDO:0005027 to epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.69 CNOT9 Achchuthan Shanmugasundram Phenotypes for gene: CNOT9 were changed from epilepsy, MONDO:0005027 to epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.69 CNOT9 Achchuthan Shanmugasundram Phenotypes for gene: CNOT9 were changed from intellectual disability, MONDO:0001071 to epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.68 CNOT9 Achchuthan Shanmugasundram edited their review of gene: CNOT9: Changed phenotypes to: epilepsy, MONDO:0005027
Intellectual disability v5.217 CNOT9 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: CNOT9.
Intellectual disability v5.217 CNOT9 Achchuthan Shanmugasundram Classified gene: CNOT9 as Amber List (moderate evidence)
Intellectual disability v5.217 CNOT9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (seven unrelated cases) for this gene to be promoted to Green at the next major update.
Intellectual disability v5.217 CNOT9 Achchuthan Shanmugasundram Gene: cnot9 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.68 CNOT9 Achchuthan Shanmugasundram gene: CNOT9 was added
gene: CNOT9 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CNOT9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CNOT9 were set to 37092538
Phenotypes for gene: CNOT9 were set to intellectual disability, MONDO:0001071
Review for gene: CNOT9 was set to GREEN
Added comment: PMID:37092538 - Seven unrelated individuals with de novo variants in CNOT9 gene (one individual each with variants p.Arg46Gly, p.Pro131Leu and p.Arg227His and four individuals with p.Arg292Trp) were reported with a neurodevelopmental disorder. All affected persons have intellectual disability (three severe, three mild and one unclassified) and five of them have seizures.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.216 CNOT9 Achchuthan Shanmugasundram gene: CNOT9 was added
gene: CNOT9 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: CNOT9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CNOT9 were set to 37092538
Phenotypes for gene: CNOT9 were set to intellectual disability, MONDO:0001071
Review for gene: CNOT9 was set to GREEN
Added comment: PMID:37092538 - Seven unrelated individuals with de novo variants in CNOT9 gene (one individual each with variants p.Arg46Gly, p.Pro131Leu and p.Arg227His and four individuals with p.Arg292Trp) were reported with a neurodevelopmental disorder. All affected persons have intellectual disability (three severe, three mild and one unclassified) and five of them have seizures.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v3.23 SLC30A9 Achchuthan Shanmugasundram Classified gene: SLC30A9 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.23 SLC30A9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with childhood onset dystonia or choreoathetosis reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Childhood onset dystonia, chorea or related movement disorder v3.23 SLC30A9 Achchuthan Shanmugasundram Gene: slc30a9 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.22 SLC30A9 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: SLC30A9.
Childhood onset dystonia, chorea or related movement disorder v3.22 SLC30A9 Achchuthan Shanmugasundram gene: SLC30A9 was added
gene: SLC30A9 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: SLC30A9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A9 were set to 28334855; 34716203; 37041080
Phenotypes for gene: SLC30A9 were set to Birk-Landau-Perez syndrome, OMIM:617595
Review for gene: SLC30A9 was set to GREEN
Added comment: PMID:28334855 - Six patients from a large multigenerational Bedouin kindred had onset of different combinations of intellectual disability, muscle weakness, oculomotor apraxia, and nephropathy in early childhood and they were identified with a homozygous variant in SLC30A9 gene (c.1047_1049delGCA; p.A350del). The age of onset of movement disorder was around 1-2 years of age.

PMID:34716203 - A girl of African-American descent was identified with compound heterozygous variants in SLC30A9 gene (c.40delA & c.86_87dupCC) and was reported with a cerebrorenal syndrome. She presented around one year of age with microcephaly and global developmental delay. She also had bilateral sensorineural hearing loss and later developed dystonic movements affecting the whole body (onset was around 5-10 years of age).

PMID:37041080 - Eight individuals from four unrelated families were reported with SLC30A9-related disease and they presented with intellectual disability and progressive hyperkinetic movement disorder, associated with oculomotor apraxia and ptosis despite phenotypic variability. The two families of British Pakistani descent harboured homozygous c.1253G>T (p.Gly418Val) variant, Egyptian Palestinian family harboured homozygous c.1049delCAG (pAla350del) variant, while family of European Australian descent had compound heterozygous variants (c.1083dup/ p.Val362Cysfs*5, and c.1413A>G/ p.Ser471=). The age of onset of movement disorder in these patients ranged from around 1-2 years to 16 years of age.

This gene has been associated with relevant phenotypes in OMIM (MIM #617595), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Classified gene: SLC30A9 as Amber List (moderate evidence)
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Gene: slc30a9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Classified gene: SLC30A9 as Amber List (moderate evidence)
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Gene: slc30a9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.; to: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.; to: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Classified gene: SLC30A9 as Amber List (moderate evidence)
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Gene: slc30a9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Classified gene: SLC30A9 as Amber List (moderate evidence)
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with Intellectual disability/ global developmental delay reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
Intellectual disability v5.215 SLC30A9 Achchuthan Shanmugasundram Gene: slc30a9 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.214 SLC30A9 Achchuthan Shanmugasundram Phenotypes for gene: SLC30A9 were changed from Birk-Landau-Perez syndrome, OMIM:617595 to Birk-Landau-Perez syndrome, OMIM:617595
Intellectual disability v5.214 SLC30A9 Achchuthan Shanmugasundram Phenotypes for gene: SLC30A9 were changed from Birk-Landau-Perez syndrome, OMIM:617595 to Birk-Landau-Perez syndrome, OMIM:617595
Intellectual disability v5.213 SLC30A9 Achchuthan Shanmugasundram Phenotypes for gene: SLC30A9 were changed from Birk-Landau-Perez syndrome, OMIM:617595 to Birk-Landau-Perez syndrome, OMIM:617595
Intellectual disability v5.213 SLC30A9 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: SLC30A9.
Intellectual disability v5.213 SLC30A9 Achchuthan Shanmugasundram Phenotypes for gene: SLC30A9 were changed from Birk-Landau-Perez syndrome, OMIM:617595 to Birk-Landau-Perez syndrome, OMIM:617595
Intellectual disability v5.213 SLC30A9 Achchuthan Shanmugasundram Phenotypes for gene: SLC30A9 were changed from ?Birk-Landau-Perez syndrome 617595 to Birk-Landau-Perez syndrome, OMIM:617595
Intellectual disability v5.212 SLC30A9 Achchuthan Shanmugasundram Publications for gene: SLC30A9 were set to 28334855
Intellectual disability v5.211 SLC30A9 Achchuthan Shanmugasundram reviewed gene: SLC30A9: Rating: GREEN; Mode of pathogenicity: None; Publications: 28334855, 34716203, 37041080; Phenotypes: Birk-Landau-Perez syndrome, OMIM:617595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.17 MCOLN1 Achchuthan Shanmugasundram changed review comment from: Mucolipidosis type IV caused by biallelic variants in MCOLN1 gene ism a lysosomal disease that primarily affects the central nervous system. It manifests with severely impaired psychomotor development, and later onset, gradual neurological decline paralleled by cerebellar degeneration and neuroaxonal injury. In addition, they also manifest tetinal dystrophy, which develops in the first years of life and rapidly progresses in adolescence, leaving patients legally blind by the second decade (PMID:33965501).

The following are some of the reported cases:
PMID:17239335 - Compound heterozygous variants in MCOLN1 were identified in a patient with mucolipidosis type IV (ML IV), who had low visual acuity and cloudy corneas since 2 years of age, progressive decrease in visual acuity since the age of 9 years.
PMID:25156245 - An Italian child with ML IV was identified with homozygous MCOLN1 variants (c.395_397delCTG & c.468_474dupTTGGACC), while his parents were heterozygous for the same variants. Ophthalmological manifestations included esotropia, bilateral corneal clouding and severe myopia.
PMID:35205297 - Six patients from two Omani families with ML IV were identified with a novel variant (c.237+5G>A) in MCOLN1 gene, which is not present in control subjects screened with a high-resolution melting (HRM) assay. The patients displayed ophthalmic manifestations including corneal haziness, pigmentary retinopathy and ERG-rod cone dysfunction.

This gene has also been associated with relevant phenotypes both in OMIM (MIM #252650) and DD and eye panels of Gene2Phenotype (with 'definitive' rating). The ophthalmological manifestations including corneal clouding, progressive retinal degeneration and optic atrophy has been reported as part of the OMIM phenotype.; to: Mucolipidosis type IV caused by biallelic variants in MCOLN1 gene ism a lysosomal disease that primarily affects the central nervous system. It manifests with severely impaired psychomotor development, and later onset, gradual neurological decline paralleled by cerebellar degeneration and neuroaxonal injury. In addition, they also manifest retinal dystrophy, which develops in the first years of life and rapidly progresses in adolescence, leaving patients legally blind by the second decade (PMID:33965501).

The following are some of the reported cases:
PMID:17239335 - Compound heterozygous variants in MCOLN1 were identified in a patient with mucolipidosis type IV (ML IV), who had low visual acuity and cloudy corneas since 2 years of age, progressive decrease in visual acuity since the age of 9 years.
PMID:25156245 - An Italian child with ML IV was identified with homozygous MCOLN1 variants (c.395_397delCTG & c.468_474dupTTGGACC), while his parents were heterozygous for the same variants. Ophthalmological manifestations included esotropia, bilateral corneal clouding and severe myopia.
PMID:35205297 - Six patients from two Omani families with ML IV were identified with a novel variant (c.237+5G>A) in MCOLN1 gene, which is not present in control subjects screened with a high-resolution melting (HRM) assay. The patients displayed ophthalmic manifestations including corneal haziness, pigmentary retinopathy and ERG-rod cone dysfunction.

This gene has also been associated with relevant phenotypes both in OMIM (MIM #252650) and DD and eye panels of Gene2Phenotype (with 'definitive' rating). The ophthalmological manifestations including corneal clouding, progressive retinal degeneration and optic atrophy has been reported as part of the OMIM phenotype.
Retinal disorders v4.17 MCOLN1 Achchuthan Shanmugasundram Classified gene: MCOLN1 as Amber List (moderate evidence)
Retinal disorders v4.17 MCOLN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Siying Lin, there is sufficient evidence for this gene to be added with a green rating in this panel as patients with MCOLN1-associated mucolipidosis IV present with a limited ocular phenotype including retinal dystrophy.
Retinal disorders v4.17 MCOLN1 Achchuthan Shanmugasundram Gene: mcoln1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.16 MCOLN1 Achchuthan Shanmugasundram Publications for gene: MCOLN1 were set to 17239335; 1488220; 18326692
Retinal disorders v4.15 MCOLN1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: MCOLN1.
Retinal disorders v4.15 MCOLN1 Achchuthan Shanmugasundram reviewed gene: MCOLN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17239335, 25156245, 33965501, 35205297; Phenotypes: Mucolipidosis IV, OMIM:252650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.15 PYGM Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are four unrelated cases in support of the association of this gene to retinal disorders. Hence, this gene can be rated green in the next major update.; to: Comment on list classification: As reviewed by Siying Lin, there are four unrelated cases in support of the association of this gene to retinal disorders. Hence, this gene can be rated green in the next major update.
Retinal disorders v4.15 PYGM Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PYGM.
Tag Q3_23_NHS_review tag was added to gene: PYGM.
Retinal disorders v4.15 PYGM Achchuthan Shanmugasundram Classified gene: PYGM as Amber List (moderate evidence)
Retinal disorders v4.15 PYGM Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases in support of the association of this gene to retinal disorders. Hence, this gene can be rated green in the next major update.
Retinal disorders v4.15 PYGM Achchuthan Shanmugasundram Gene: pygm has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.14 PYGM Achchuthan Shanmugasundram Phenotypes for gene: PYGM were changed from Macular dystrophy, retinopathy to macular dystrophy, retinal, MONDO:0031166
Retinal disorders v4.13 PYGM Achchuthan Shanmugasundram Publications for gene: PYGM were set to PMID 30316539
Retinal disorders v4.12 PYGM Achchuthan Shanmugasundram reviewed gene: PYGM: Rating: GREEN; Mode of pathogenicity: None; Publications: 30316539; Phenotypes: macular dystrophy, retinal, MONDO:0031166; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v3.21 TMEM151A Achchuthan Shanmugasundram Tag Q3_23_NHS_review tag was added to gene: TMEM151A.
Childhood onset dystonia, chorea or related movement disorder v3.21 TMEM151A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence (more than 40 unrelated cases and supporting functional evidence) available in support of the association of this gene to PKD. Hence, this gene can be rated Green in the next major update.; to: Comment on list classification: There is sufficient evidence (more than 40 unrelated cases and supporting functional evidence) available in support of the association of this gene to PKD with onset in childhood/ adolescence. Hence, this gene can be rated Green in the next major update.
Childhood onset dystonia, chorea or related movement disorder v3.21 TMEM151A Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: TMEM151A.
Childhood onset dystonia, chorea or related movement disorder v3.21 TMEM151A Achchuthan Shanmugasundram Classified gene: TMEM151A as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.21 TMEM151A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (more than 40 unrelated cases and supporting functional evidence) available in support of the association of this gene to PKD. Hence, this gene can be rated Green in the next major update.
Childhood onset dystonia, chorea or related movement disorder v3.21 TMEM151A Achchuthan Shanmugasundram Gene: tmem151a has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.20 TMEM151A Achchuthan Shanmugasundram Phenotypes for gene: TMEM151A were changed from Episodic kinesigenic dyskinesia 3 to Episodic kinesigenic dyskinesia 3, OMIM:620245
Childhood onset dystonia, chorea or related movement disorder v3.19 TMEM151A Achchuthan Shanmugasundram Publications for gene: TMEM151A were set to 34518509; 34820915; 35587630; 35707035; 35727387
Childhood onset dystonia, chorea or related movement disorder v3.18 TMEM151A Achchuthan Shanmugasundram changed review comment from: PMID:34518509 - Nine individuals from three unrelated Chines families with paroxysmal kinesigenic dyskinesia (PKD) were identified with autosomal dominant variants in TMEM151A gene. In addition, 8 unrelated patients (isolated cases) with sporadic occurrence of PKD were also identified with heterozygous variants, of which three patients inherited variants from an unaffected parent, suggesting incomplete penetrance. The age of onset of symptoms ranged between 9 and 15 years. In addition, supporting mouse model and in vitro functional assays suggested loss of function as the mechanism of disease.

PMID:34820915 - 29 PRRT2-negative Chinese patients from 25 families with PKD identified with 24 heterozygous variants in TMEM151A gene. The mean age of onset of symptoms was 12.93 years, with 13 patients reported with spontaneous remission of the disease around 21 years of age.

PMID:35587630 - De novo missense variant in TMEM151A was identified in a French man with PKD and he presented with brief attacks of dystonia after 16 years of age.

PMID:35707035 - Screening of patients with PRRT2-negative PKD and other movement disorders identified two novel variants in TMEM151A gene in two patients with PKD.

PMID:35727387 - Heterozygous missense variant was identified in four affected members of a 3-generation Chinese family with PKD and the variant segregated with the disorder in the family.


This gene has been associated with relevant phenotype in OMIM (MIM #620245), but not in Gene2Phenotype.; to: PMID:34518509 - Nine individuals from three unrelated Chines families with paroxysmal kinesigenic dyskinesia (PKD) were identified with autosomal dominant variants in TMEM151A gene. In addition, 8 unrelated patients (isolated cases) with sporadic occurrence of PKD were also identified with heterozygous variants, of which three patients inherited variants from an unaffected parent, suggesting incomplete penetrance. The age of onset of symptoms ranged between 9 and 15 years. In addition, supporting mouse model and in vitro functional assays suggested loss of function as the mechanism of disease.

PMID:34820915 - 29 PRRT2-negative Chinese patients from 25 families with PKD identified with 24 heterozygous variants in TMEM151A gene. The mean age of onset of symptoms was 12.93 years, with 13 patients reported with spontaneous remission of the disease around 21 years of age.

PMID:35587630 - De novo missense variant in TMEM151A was identified in a French man with PKD and he presented with brief attacks of dystonia after 16 years of age.

PMID:35707035 - Screening of patients with PRRT2-negative PKD and other movement disorders identified two novel variants in TMEM151A gene in two patients with PKD.

PMID:35727387 - Heterozygous missense variant was identified in four affected members of a 3-generation Chinese family with PKD and the variant segregated with the disorder in the family.

PMID:36724570 - Three patients presenting with PKD were identified with different TMEM151A variants.

This gene has been associated with relevant phenotype in OMIM (MIM #620245), but not in Gene2Phenotype.
Childhood onset dystonia, chorea or related movement disorder v3.18 TMEM151A Achchuthan Shanmugasundram edited their review of gene: TMEM151A: Changed publications to: 34518509, 34820915, 35587630, 35707035, 35727387, 36724570
Childhood onset dystonia, chorea or related movement disorder v3.18 TMEM151A Achchuthan Shanmugasundram Publications for gene: TMEM151A were set to (PMID: 34518509; 35707035; 36724570; 34820915)
Childhood onset dystonia, chorea or related movement disorder v3.17 TMEM151A Achchuthan Shanmugasundram reviewed gene: TMEM151A: Rating: GREEN; Mode of pathogenicity: None; Publications: 34518509, 34820915, 35587630, 35707035, 35727387; Phenotypes: Episodic kinesigenic dyskinesia 3, OMIM:620245; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder - nuclear genes v3.33 PPOX Achchuthan Shanmugasundram changed review comment from: As reviewed by Zornitza Stark and suggested in PMID:25778941, Variegate porphyria (VP) should be included in this panel.

Autosomal dominat variegate porphyria (VP):

VP is usually caused by autosomal dominant variants in PPOX gene in the majority of the cases.

PMID:30476629 - Eight unrelated individuals with seven different variants in heterozygous state were reported with VP.

Autosomal dominant variants in this gene have also been associated with VP in OMIM (MIM #176200).

Autosomal recessive variegate porphyria (VP):

PMID:9540991 - A severely affected female proband with recessive VP was identified with two missense compound heterozygous variants in PPOX gene (p.Gly169Glu & p.Gly358Arg), as detected by heteroduplex analysis, automated sequencing, and allele specific oligonucleotide hybridization.

PMID:10870850 - Two unrelated South African cases with variegate porphyria were reported with onset of the disease usually in infancy and with severe skin manifestations. The variant detection included combined SSCP-heteroduplex analysis followed by direct sequencing and both had the common p.Arg59Trp variant, while the other variant was p.Tyr348Cys in one and p.Arg138Pro in the other.

PMID:32247286 - A case of VP was reported from a family with only cutaneous manifestations and was identified with two heterozygous missense variants in PPOX gene (p.Gly41Cys and p.Trp42Arg). The same variants were identified in patient's mother who had skin lesions, whereas father had no clinical involvement and did not have any of these variants. The familly study showed that the two variants occur in cis on the same allele.

PMID:33159949 - A novel homozygous variant in PPOX gene (c.808G>T) was identified in a patient with autosomal recessive form of VP.

Overall, the autosomal recessive form of VP usually occurs early in in fancy and have markedly reduced levels of protoporphyrinogen oxidase than autosomal dominant form. Autosomal recessive VP has not yet been reported in OMIM.; to: As reviewed by Zornitza Stark in 'Mitochondrial disorders' panel and suggested in PMID:25778941, Variegate porphyria (VP) should be included in this panel.

Autosomal dominat variegate porphyria (VP):

VP is usually caused by autosomal dominant variants in PPOX gene in the majority of the cases.

PMID:30476629 - Eight unrelated individuals with seven different variants in heterozygous state were reported with VP.

Autosomal dominant variants in this gene have also been associated with VP in OMIM (MIM #176200).

Autosomal recessive variegate porphyria (VP):

PMID:9540991 - A severely affected female proband with recessive VP was identified with two missense compound heterozygous variants in PPOX gene (p.Gly169Glu & p.Gly358Arg), as detected by heteroduplex analysis, automated sequencing, and allele specific oligonucleotide hybridization.

PMID:10870850 - Two unrelated South African cases with variegate porphyria were reported with onset of the disease usually in infancy and with severe skin manifestations. The variant detection included combined SSCP-heteroduplex analysis followed by direct sequencing and both had the common p.Arg59Trp variant, while the other variant was p.Tyr348Cys in one and p.Arg138Pro in the other.

PMID:32247286 - A case of VP was reported from a family with only cutaneous manifestations and was identified with two heterozygous missense variants in PPOX gene (p.Gly41Cys and p.Trp42Arg). The same variants were identified in patient's mother who had skin lesions, whereas father had no clinical involvement and did not have any of these variants. The familly study showed that the two variants occur in cis on the same allele.

PMID:33159949 - A novel homozygous variant in PPOX gene (c.808G>T) was identified in a patient with autosomal recessive form of VP.

Overall, the autosomal recessive form of VP usually occurs early in in fancy and have markedly reduced levels of protoporphyrinogen oxidase than autosomal dominant form. Autosomal recessive VP has not yet been reported in OMIM.
Possible mitochondrial disorder - nuclear genes v3.33 PPOX Achchuthan Shanmugasundram Classified gene: PPOX as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.33 PPOX Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than three unrelated cases each with both monoallelic and biallelic variants in PPOX gene. Hence, this gene should be promoted to Green at the next GMS update and the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.
Possible mitochondrial disorder - nuclear genes v3.33 PPOX Achchuthan Shanmugasundram Gene: ppox has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.32 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to
Possible mitochondrial disorder - nuclear genes v3.31 PPOX Achchuthan Shanmugasundram Mode of inheritance for gene: PPOX was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.30 PPOX Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PPOX.
Possible mitochondrial disorder - nuclear genes v3.30 PPOX Achchuthan Shanmugasundram reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 9540991, 10870850, 25778941, 30476629, 32247286, 33159949; Phenotypes: Porphyria variegata, OMIM:176200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.37 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to
Hereditary neuropathy or pain disorder v3.36 PPOX Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: Comment on mode of inheritance: There are at least three cases of variegate porphyria reported with biallelic variants in PPOX gene and sensory neuropathy. Hence, the MOI should be updated from "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" in the next GMS review.
Hereditary neuropathy or pain disorder v3.36 PPOX Achchuthan Shanmugasundram Mode of inheritance for gene: PPOX was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.35 PPOX Achchuthan Shanmugasundram Tag Q3_23_MOI tag was added to gene: PPOX.
Hereditary neuropathy or pain disorder v3.35 PPOX Achchuthan Shanmugasundram reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 8290408, 10870850, 11286631; Phenotypes: Porphyria variegata, OMIM:176200, Sensory neuropathy, HP:0000763; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.470 PPOX Achchuthan Shanmugasundram Mode of inheritance for gene: PPOX was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.469 PPOX Achchuthan Shanmugasundram Tag Q3_23_MOI was removed from gene: PPOX.
Hereditary neuropathy v1.469 PPOX Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There are at least three cases of variegate porphyria reported with biallelic variants in PPOX gene and sensory neuropathy. Hence, the MOI can be updated from "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" in the next GMS review.; to: Comment on mode of inheritance: There are at least three cases of variegate porphyria reported with biallelic variants in PPOX gene and sensory neuropathy. Hence, the MOI should be updated from "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal".
Hereditary neuropathy v1.469 PPOX Achchuthan Shanmugasundram Tag Q3_23_MOI tag was added to gene: PPOX.
Hereditary neuropathy v1.469 PPOX Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least three cases of variegate porphyria reported with biallelic variants in PPOX gene and sensory neuropathy. Hence, the MOI can be updated from "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" in the next GMS review.
Hereditary neuropathy v1.469 PPOX Achchuthan Shanmugasundram Mode of inheritance for gene: PPOX was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy v1.468 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to 8290408; 10870850; 11286631
Hereditary neuropathy v1.467 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to
Hereditary neuropathy v1.466 PPOX Achchuthan Shanmugasundram edited their review of gene: PPOX: Changed rating: GREEN
Hereditary neuropathy v1.466 PPOX Achchuthan Shanmugasundram reviewed gene: PPOX: Rating: ; Mode of pathogenicity: None; Publications: 8290408, 10870850, 11286631; Phenotypes: Porphyria variegata, OMIM:176200, Sensory neuropathy, HP:0000763; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v4.62 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to 9540991; 9811936; 10870850; 12859407; 25778941; 30476629; 32247286; 33159949
Mitochondrial disorders v4.62 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to
Mitochondrial disorders v4.61 PPOX Achchuthan Shanmugasundram Mode of inheritance for gene: PPOX was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v4.60 PPOX Achchuthan Shanmugasundram Deleted their comment
Mitochondrial disorders v4.60 PPOX Achchuthan Shanmugasundram Classified gene: PPOX as Amber List (moderate evidence)
Mitochondrial disorders v4.60 PPOX Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than three unrelated cases each with both monoallelic and biallelic variants in PPOX gene. Hence, this gene should be promoted to Green at the next GMS update and the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.
Mitochondrial disorders v4.60 PPOX Achchuthan Shanmugasundram Gene: ppox has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.60 PPOX Achchuthan Shanmugasundram Classified gene: PPOX as Amber List (moderate evidence)
Mitochondrial disorders v4.60 PPOX Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than three unrelated cases each with both monoallelic and biallelic variants in PPOX gene. Hence, this gene should be promoted to Green at the next GMS update and the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.
Mitochondrial disorders v4.60 PPOX Achchuthan Shanmugasundram Gene: ppox has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.59 PPOX Achchuthan Shanmugasundram Tag Q3_23_MOI was removed from gene: PPOX.
Tag Q3_23_promote_green tag was added to gene: PPOX.
Mitochondrial disorders v4.59 PPOX Achchuthan Shanmugasundram Tag Q3_23_MOI tag was added to gene: PPOX.
Mitochondrial disorders v4.59 PPOX Achchuthan Shanmugasundram edited their review of gene: PPOX: Changed publications to: 9540991, 10870850, 25778941, 30476629, 32247286, 33159949
Mitochondrial disorders v4.59 PPOX Achchuthan Shanmugasundram changed review comment from: Autosomal dominat variegate porphyria (VP):

VP is usually caused by autosomal dominant variants in PPOX gene in the majority of the cases.

PMID:30476629 - Eight unrelated individuals with seven different variants in heterozygous state were reported with VP.

Autosomal dominant variants in this gene have also been associated with VP in OMIM (MIM #176200).

Autosomal recessive variegate porphyria (VP):

PMID:9540991 - A severely affected female proband with recessive VP was identified with two missense compound heterozygous variants in PPOX gene (p.Gly169Glu & p.Gly358Arg), as detected by heteroduplex analysis, automated sequencing, and allele specific oligonucleotide hybridization.

PMID:10870850 - Two unrelated South African cases with variegate porphyria were reported with onset of the disease usually in infancy and with severe skin manifestations. The variant detection included combined SSCP-heteroduplex analysis followed by direct sequencing and both had the common p.Arg59Trp variant, while the other variant was p.Tyr348Cys in one and p.Arg138Pro in the other.

PMID:32247286 - A case of VP was reported from a family with only cutaneous manifestations and was identified with two heterozygous missense variants in PPOX gene (p.Gly41Cys and p.Trp42Arg). The same variants were identified in patient's mother who had skin lesions, whereas father had no clinical involvement and did not have any of these variants. The familly study showed that the two variants occur in cis on the same allele.

PMID:33159949 - A novel homozygous variant in PPOX gene (c.808G>T) was identified in a patient with autosomal recessive form of VP.

Overall, the autosomal recessive form of VP usually occurs early in in fancy and have markedly reduced levels of protoporphyrinogen oxidase than autosomal dominant form. Autosomal recessive VP has not yet been reported in OMIM.
; to: As reviewed by Zornitza Stark and suggested in PMID:25778941, Variegate porphyria (VP) should be included in this panel.

Autosomal dominat variegate porphyria (VP):

VP is usually caused by autosomal dominant variants in PPOX gene in the majority of the cases.

PMID:30476629 - Eight unrelated individuals with seven different variants in heterozygous state were reported with VP.

Autosomal dominant variants in this gene have also been associated with VP in OMIM (MIM #176200).

Autosomal recessive variegate porphyria (VP):

PMID:9540991 - A severely affected female proband with recessive VP was identified with two missense compound heterozygous variants in PPOX gene (p.Gly169Glu & p.Gly358Arg), as detected by heteroduplex analysis, automated sequencing, and allele specific oligonucleotide hybridization.

PMID:10870850 - Two unrelated South African cases with variegate porphyria were reported with onset of the disease usually in infancy and with severe skin manifestations. The variant detection included combined SSCP-heteroduplex analysis followed by direct sequencing and both had the common p.Arg59Trp variant, while the other variant was p.Tyr348Cys in one and p.Arg138Pro in the other.

PMID:32247286 - A case of VP was reported from a family with only cutaneous manifestations and was identified with two heterozygous missense variants in PPOX gene (p.Gly41Cys and p.Trp42Arg). The same variants were identified in patient's mother who had skin lesions, whereas father had no clinical involvement and did not have any of these variants. The familly study showed that the two variants occur in cis on the same allele.

PMID:33159949 - A novel homozygous variant in PPOX gene (c.808G>T) was identified in a patient with autosomal recessive form of VP.

Overall, the autosomal recessive form of VP usually occurs early in in fancy and have markedly reduced levels of protoporphyrinogen oxidase than autosomal dominant form. Autosomal recessive VP has not yet been reported in OMIM.
Mitochondrial disorders v4.59 PPOX Achchuthan Shanmugasundram changed review comment from: PMID:30476629 - Eight unrelated individuals with seven different variants in heterozygous state were reported with Variegate porphyria (VP).

PMID:32247286 - A case of VP was reported from a family with only cutaneous manifestations and was identified with two heterozygous missense variants in PPOX gene (p.Gly41Cys and p.Trp42Arg). The same variants were identified in patient's mother who had skin lesions, whereas father had no clinical involvement and did not have any of these variants. The familly study showed that the two variants occur in cis on the same allele.

Autosomal dominant variants in this gene have been associated with Variegate porphyria in OMIM (MIM #176200).; to: Autosomal dominat variegate porphyria (VP):

VP is usually caused by autosomal dominant variants in PPOX gene in the majority of the cases.

PMID:30476629 - Eight unrelated individuals with seven different variants in heterozygous state were reported with VP.

Autosomal dominant variants in this gene have also been associated with VP in OMIM (MIM #176200).

Autosomal recessive variegate porphyria (VP):

PMID:9540991 - A severely affected female proband with recessive VP was identified with two missense compound heterozygous variants in PPOX gene (p.Gly169Glu & p.Gly358Arg), as detected by heteroduplex analysis, automated sequencing, and allele specific oligonucleotide hybridization.

PMID:10870850 - Two unrelated South African cases with variegate porphyria were reported with onset of the disease usually in infancy and with severe skin manifestations. The variant detection included combined SSCP-heteroduplex analysis followed by direct sequencing and both had the common p.Arg59Trp variant, while the other variant was p.Tyr348Cys in one and p.Arg138Pro in the other.

PMID:32247286 - A case of VP was reported from a family with only cutaneous manifestations and was identified with two heterozygous missense variants in PPOX gene (p.Gly41Cys and p.Trp42Arg). The same variants were identified in patient's mother who had skin lesions, whereas father had no clinical involvement and did not have any of these variants. The familly study showed that the two variants occur in cis on the same allele.

PMID:33159949 - A novel homozygous variant in PPOX gene (c.808G>T) was identified in a patient with autosomal recessive form of VP.

Overall, the autosomal recessive form of VP usually occurs early in in fancy and have markedly reduced levels of protoporphyrinogen oxidase than autosomal dominant form. Autosomal recessive VP has not yet been reported in OMIM.
Mitochondrial disorders v4.59 PPOX Achchuthan Shanmugasundram edited their review of gene: PPOX: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v4.59 PPOX Achchuthan Shanmugasundram reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 30476629, 32247286; Phenotypes: Porphyria variegata, OMIM:176200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v4.10 PTPRQ Achchuthan Shanmugasundram changed review comment from: PMID:29309402 - A heterozygous nonsense variant (c.6881G>A; p.Trp2294Ter) was identified in a four-generation German family with nonsyndromic mild to severe hearing loss of the mid- to high frequencies and onset from early childhood to second decade in seven members.

PMID:31655630 - The same variant (c.6881G>A; p.Trp2294Ter) was identified in a five-generation Polish family with autosomal dominant non-syndromic hearing loss (ADNSHL). Using genome-wide linkage analysis, the authors also found that the studied Polish family and the original German family derive from a common ancestor.

PMID:33229591 - PTPRQ variants p.Gly383Glu and p.Arg841Trp were identified in multiplex family age-related hearing loss (mARHL) cases, while p.Ser1022Arg, c.4286-1G>T and p.Leu879Argfs*20 were identified with simplex/sporadic age-related hearing loss (sARHL) cases. However, p.Ser321Cys was identified in control cases with normal hearing.; to: PMID:29309402 - A heterozygous nonsense variant (c.6881G>A; p.Trp2294Ter) was identified in a four-generation German family with nonsyndromic mild to severe hearing loss of the mid- to high frequencies and onset from early childhood to second decade in seven members.

PMID:31655630 - The same variant (c.6881G>A; p.Trp2294Ter) was identified in a five-generation Polish family with autosomal dominant non-syndromic hearing loss (ADNSHL). Using genome-wide linkage analysis, the authors also found that the studied Polish family and the original German family derive from a common ancestor.

PMID:33229591 - PTPRQ variants p.Gly383Glu and p.Arg841Trp were identified in multiplex family age-related hearing loss (mARHL) cases, while p.Ser1022Arg, c.4286-1G>T and p.Leu879Argfs*20 were identified with simplex/sporadic age-related hearing loss (sARHL) cases. However, p.Ser321Cys was identified in control cases with normal hearing.

This gene has been associated with hearing loss caused by both autosomal dominant (MIM #617663) and autosomal recessive (MIM #613391) inheritance in OMIM.
Monogenic hearing loss v4.10 PTPRQ Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there are sufficient cases/ variants reported with monoallelic inheritance and hearing loss, the MOI should be changed from "BIALLELIC, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" in the next major review.
Monogenic hearing loss v4.10 PTPRQ Achchuthan Shanmugasundram Mode of inheritance for gene: PTPRQ was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v4.9 PTPRQ Achchuthan Shanmugasundram Tag Q3_23_MOI tag was added to gene: PTPRQ.
Monogenic hearing loss v4.9 PTPRQ Achchuthan Shanmugasundram reviewed gene: PTPRQ: Rating: GREEN; Mode of pathogenicity: None; Publications: 29309402, 31655630, 33229591; Phenotypes: Deafness, autosomal dominant 73, OMIM:617663, Deafness, autosomal recessive 84A, OMIM:613391; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal ciliopathies v3.9 PMM2 Eleanor Williams Tag Q3_23_expert_review tag was added to gene: PMM2.
Skeletal ciliopathies v3.9 PMM2 Eleanor Williams Tag Q3_23_demote_red tag was added to gene: PMM2.
Skeletal ciliopathies v3.9 PMM2 Eleanor Williams commented on gene: PMM2: After reviewing the literature no patients were found with a skeletal phenotype so demotion to red on this panel is recommended. This has been confirmed with a Genomics England clinician. It is represented on the other ciliopathy panels, so shouldn't be missed for relevant phenotypes. It was initially added as a ciliopathy mimic.
Skeletal dysplasia v4.10 EN1 Eleanor Williams changed review comment from: The Genomics England clinical team confirm that the rating of this gene should currently be amber based on 1 case and a mouse model.; to: The Genomics England clinical team confirm that the rating of this gene should currently be amber based on 1 case and a mouse model. It has been additionally added to the 'Fetal anomalies' and 'Ataxia and cerebellar anomalies - narrow panel' panels based on the phenotype.

If more cases with intellectual disability/seizures are reported then it could be additionally added to those panels at that time.
Ataxia and cerebellar anomalies - narrow panel v4.21 EN1 Eleanor Williams Tag watchlist tag was added to gene: EN1.
Ataxia and cerebellar anomalies - narrow panel v4.21 EN1 Eleanor Williams commented on gene: EN1: This gene was copied from the Skeletal dysplasia panel to the Ataxia and cerebellar anomalies - narrow panel panel. The Genomics England clinical team have agreed that Fetal anomalies is an appropriate panel for this gene and the rating should currently be amber.
Skeletal dysplasia v4.10 EN1 Eleanor Williams Tag watchlist tag was added to gene: EN1.
Fetal anomalies v3.92 EN1 Eleanor Williams Tag watchlist tag was added to gene: EN1.
Fetal anomalies v3.92 EN1 Eleanor Williams commented on gene: EN1: This gene was copied from the Skeletal dysplasia panel to the Fetal anomalies panel. The Genomics England clinical team have agreed that Fetal anomalies is an appropriate panel for this gene and the rating should currently be amber.
Fetal anomalies v3.92 EN1 Eleanor Williams Entity copied from Skeletal dysplasia v4.10
Fetal anomalies v3.92 EN1 Eleanor Williams gene: EN1 was added
gene: EN1 was added to Fetal anomalies. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: EN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EN1 were set to 33568816
Phenotypes for gene: EN1 were set to ENDOVE syndrome, limb-only type, MIM# 619217; ENDOVE syndrome, limb-brain type, MIM# 619218
Ataxia and cerebellar anomalies - narrow panel v4.21 EN1 Eleanor Williams Entity copied from Skeletal dysplasia v4.10
Ataxia and cerebellar anomalies - narrow panel v4.21 EN1 Eleanor Williams gene: EN1 was added
gene: EN1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: EN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EN1 were set to 33568816
Phenotypes for gene: EN1 were set to ENDOVE syndrome, limb-only type, MIM# 619217; ENDOVE syndrome, limb-brain type, MIM# 619218
Skeletal dysplasia v4.10 EN1 Eleanor Williams commented on gene: EN1: The Genomics England clinical team confirm that the rating of this gene should currently be amber based on 1 case and a mouse model.
Mosaic skin disorders - deep sequencing v2.9 FGFR2 Arina Puzriakova Phenotypes for gene: FGFR2 were changed from Epdermal naevi to Keratinocytic epidermal naevi (KENs); Naevoid acanthosis nigricans; RAVEN (round and velvety epidermal naevus)
Vascular skin disorders v1.51 EPHB4 Arina Puzriakova Phenotypes for gene: EPHB4 were changed from CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2, OMIM:618196 to Capillary malformation-arteriovenous malformation 2, OMIM:618196
Hereditary haemorrhagic telangiectasia v3.2 EPHB4 Arina Puzriakova Phenotypes for gene: EPHB4 were changed from Capillary malformation-arteriovenous malformation 2, 618196; Capillary malformation, epistaxis, telangiectasia, cerebral AVM to Capillary malformation-arteriovenous malformation 2, OMIM:618196; Capillary malformation, epistaxis, telangiectasia, cerebral AVM
Primary lymphoedema v3.3 EPHB4 Arina Puzriakova Phenotypes for gene: EPHB4 were changed from Lymphatic malformation 7 617300 to Lymphatic malformation 7, OMIM:617300
Fetal anomalies v3.91 EPHB4 Arina Puzriakova Phenotypes for gene: EPHB4 were changed from hydrops fetalis gene to Lymphatic malformation 7, OMIM:617300; hydrops fetalis
Fetal hydrops v1.61 EPHB4 Arina Puzriakova Mode of inheritance for gene: EPHB4 was changed from MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal hydrops v1.60 EPHB4 Arina Puzriakova Phenotypes for gene: EPHB4 were changed from Lymphatic malformation 7, MIM#617300 to Lymphatic malformation 7, OMIM:617300
Fetal hydrops v1.59 EPHB4 Arina Puzriakova Classified gene: EPHB4 as Green List (high evidence)
Fetal hydrops v1.59 EPHB4 Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence to support hydrops fetalis association as part of MIM:617300, with 3 variants listed in OMIM from 3 families, each with multiple affected individuals (PMIDs: 27400125 and 29905864). Already Green on Fetal anomalies GMS panel.
Fetal hydrops v1.59 EPHB4 Arina Puzriakova Gene: ephb4 has been classified as Green List (High Evidence).
Mosaic skin disorders - deep sequencing v2.8 EPHB4 Arina Puzriakova Tag watchlist tag was added to gene: EPHB4.
Mosaic skin disorders - deep sequencing v2.8 EPHB4 Arina Puzriakova Classified gene: EPHB4 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.8 EPHB4 Arina Puzriakova Added comment: Comment on list classification: Rating Amber for now as only a single case with mosaicism has been reported to date. The patients phenotype was comparable to germline cases but another independent report or functional studies of the variant would help corroborate this association before classifying as diagnostic-grade.
Mosaic skin disorders - deep sequencing v2.8 EPHB4 Arina Puzriakova Gene: ephb4 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v2.7 EPHB4 Arina Puzriakova Publications for gene: EPHB4 were set to PMID: 30760892
Mosaic skin disorders - deep sequencing v2.6 EPHB4 Arina Puzriakova Phenotypes for gene: EPHB4 were changed from Capillary malformation-arteriovenous malformation 2 (MIM 618196); Lymphatic malformation 7 (MIM 617300) to Capillary malformation-arteriovenous malformation 2, OMIM:618196
Mosaic skin disorders - deep sequencing v2.5 EPHB4 Arina Puzriakova commented on gene: EPHB4
Beckwith-Wiedemann syndrome v0.2 CDKN1C Achchuthan Shanmugasundram Mode of inheritance for gene: CDKN1C was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Beckwith-Wiedemann syndrome v0.1 CDKN1C Achchuthan Shanmugasundram edited their review of gene: CDKN1C: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Infantile nystagmus v1.10 DAGLA Achchuthan Shanmugasundram Classified gene: DAGLA as Green List (high evidence)
Infantile nystagmus v1.10 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than three unrelated cases with infantile nystagmus and hence this gene can be promoted to green in this panel.
Infantile nystagmus v1.10 DAGLA Achchuthan Shanmugasundram Gene: dagla has been classified as Green List (High Evidence).
Infantile nystagmus v1.9 DAGLA Achchuthan Shanmugasundram Phenotypes for gene: DAGLA were changed from developmental delay; ataxia; complex oculomotor abnormality (nystagmus) to congenital nystagmus, MONDO:0005712
Infantile nystagmus v1.8 DAGLA Achchuthan Shanmugasundram Publications for gene: DAGLA were set to PMID: 35737950
Infantile nystagmus v1.7 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Infantile nystagmus v1.6 DAGLA Achchuthan Shanmugasundram reviewed gene: DAGLA: 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: 35737950; Phenotypes: congenital nystagmus, MONDO:0005712; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia v1.330 DAGLA Achchuthan Shanmugasundram changed review comment from: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. All nine children had ataxia and the age of these children ranged between 4 and 15 years of age. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950).

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.; to: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. All nine children had ataxia and the age of these children ranged between 4 and 15 years of age. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950).

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Epidermolysis bullosa and congenital skin fragility v2.4 ATP2A2 Arina Puzriakova Phenotypes for gene: ATP2A2 were changed from Darier disease, OMIM:124200 to Darier-White disease, OMIM:124200
Mitochondrial disorders v4.59 ANO10 Sarah Leigh Phenotypes for gene: ANO10 were changed from Spinocerebellar ataxia, autosomal recessive 10, 613728 to Spinocerebellar ataxia, autosomal recessive 10, OMIM:613728; autosomal recessive spinocerebellar ataxia 10, MONDO:0013392
Mitochondrial disorders v4.58 ANO10 Sarah Leigh Publications for gene: ANO10 were set to
Mitochondrial disorders v4.57 ANO10 Sarah Leigh Tag Q3_23_expert_review tag was added to gene: ANO10.
Mitochondrial disorders v4.57 BTD Sarah Leigh Tag Q3_23_expert_review tag was added to gene: BTD.
Mucopolysaccharidosis type IH or S v0.2 Achchuthan Shanmugasundram Panel name changed from Mucopolysaccharidosis type IH/S to Mucopolysaccharidosis type IH or S
Mucolipidosis II and III Alpha or Beta v0.2 Achchuthan Shanmugasundram Panel name changed from Mucolipidosis II and III Alpha/Beta to Mucolipidosis II and III Alpha or Beta
Mitochondrial disorders v4.57 ANO10 Sarah Leigh reviewed gene: ANO10: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mitochondrial disorders v4.57 BTD Sarah Leigh reviewed gene: BTD: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia v1.330 DAGLA Achchuthan Shanmugasundram Classified gene: DAGLA as Green List (high evidence)
Hereditary ataxia v1.330 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are eight unrelated cases associating monoallelic variants in DAGLA with ataxia. Hence, this gene can be rated Green.
Hereditary ataxia v1.330 DAGLA Achchuthan Shanmugasundram Gene: dagla has been classified as Green List (High Evidence).
Hereditary ataxia v1.329 DAGLA Achchuthan Shanmugasundram Phenotypes for gene: DAGLA were changed from developmental delay; ataxia; complex oculomotor abnormality to Ataxia, HP:0001251
Hereditary ataxia v1.328 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Hereditary ataxia v1.327 DAGLA Achchuthan Shanmugasundram Publications for gene: DAGLA were set to PMID: 35737950
Hereditary ataxia v1.326 DAGLA Achchuthan Shanmugasundram reviewed gene: DAGLA: 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: 35737950; Phenotypes: Ataxia, HP:0001251; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v4.57 BTD Sarah Leigh Phenotypes for gene: BTD were changed from Biotinidase deficiency to Biotinidase deficiency, OMIM:253260; biotinidase deficiency, MONDO:0009665
Ataxia and cerebellar anomalies - narrow panel v4.20 DAGLA Achchuthan Shanmugasundram Classified gene: DAGLA as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.20 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are eight unrelated cases associating monoallelic variants in DAGLA with ataxia. Hence, this gene should be promoted to Green rating at the next major review.
Ataxia and cerebellar anomalies - narrow panel v4.20 DAGLA Achchuthan Shanmugasundram Gene: dagla has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA 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
Intellectual disability v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA 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
Intellectual disability v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA 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
Ataxia and cerebellar anomalies - narrow panel v4.19 DAGLA Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: DAGLA.
Intellectual disability v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA 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
Intellectual disability v5.211 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA 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
Intellectual disability v5.210 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA 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
Ataxia and cerebellar anomalies - narrow panel v4.19 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA 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
Intellectual disability v5.210 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA 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
Intellectual disability v5.210 DAGLA Achchuthan Shanmugasundram Mode of pathogenicity for gene: DAGLA was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram edited their review of gene: DAGLA: 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
Ataxia and cerebellar anomalies - narrow panel v4.18 DAGLA Achchuthan Shanmugasundram edited their review of gene: DAGLA: 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
Ataxia and cerebellar anomalies - narrow panel v4.18 DAGLA Achchuthan Shanmugasundram gene: DAGLA was added
gene: DAGLA was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: DAGLA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DAGLA were set to 35737950
Phenotypes for gene: DAGLA were set to Ataxia, HP:0001251
Review for gene: DAGLA was set to GREEN
Added comment: There are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. All nine children had ataxia and the age of these children ranged between 4 and 15 years of age. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950).

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram changed review comment from: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950).; to: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950).

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Mosaic skin disorders - deep sequencing v2.5 ATP2A2 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: ATP2A2.
Tag Q3_23_NHS_review tag was added to gene: ATP2A2.
Mosaic skin disorders - deep sequencing v2.5 ATP2A2 Arina Puzriakova Classified gene: ATP2A2 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.5 ATP2A2 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 6 unrelated cases of mosaic Darier disease reported in literature. ATP2A2 is associated with a relevant phenotype in OMIM that also mentions somatic mosaic disease.
Mosaic skin disorders - deep sequencing v2.5 ATP2A2 Arina Puzriakova Gene: atp2a2 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v2.4 ATP2A2 Arina Puzriakova Phenotypes for gene: ATP2A2 were changed from to Segmental Darier disease OMIM:124200; Darier-White disease OMIM:124200; Acrokeratosis verruciformis, OMIM:101900
Mosaic skin disorders - deep sequencing v2.3 ATP2A2 Arina Puzriakova Publications for gene: ATP2A2 were set to
Segmental overgrowth disorders - Deep sequencing v3.6 ARAF Arina Puzriakova Tag treatable was removed from gene: ARAF.
Tag Q3_23_NHS_review tag was added to gene: ARAF.
Mosaic skin disorders - deep sequencing v2.2 ARAF Arina Puzriakova Tag treatable tag was added to gene: ARAF.
Segmental overgrowth disorders - Deep sequencing v3.6 ARAF Arina Puzriakova Tag treatable tag was added to gene: ARAF.
Segmental overgrowth disorders - Deep sequencing v3.6 ARAF Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Tom Cullup (GOSH). ARAF is not currently associated with any phenotype in OMIM or G2P. Although only two patients have been reported with the same missense variant, functional studies including an animal model provide strong support of pathogenicity (outlined below). Evidence of this variant specific gene-disease relationship is sufficiently compelling but the phenotype is more within scope of the R110 Segmental overgrowth disorders – Deep sequencing panel. Therefore rating as amber on this panel and green on R110.

- PMID: 31263281 (2019):
To date, only two unrelated patients have been reported with the same missense GoF variant in ARAF (c.640T>C:p.S214P) who both had a complex lymphatic anomaly (no haplotype analysis was done). Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions. A zebrafish model recapitulated the lymphatic phenotype. The cellular, zebrafish and patient clinical phenotypes were all rescued with with a MEK inhibitor.; to: Comment on list classification: New gene added by Tom Cullup (GOSH). ARAF is not currently associated with any phenotype in OMIM or G2P. Although only two patients have been reported with the same missense variant, functional studies including an animal model provide strong support of pathogenicity (outlined below). Evidence of this variant specific gene-disease relationship is sufficiently compelling to rate this gene as green at the next GMS panel update.

- PMID: 31263281 (2019):
To date, only two unrelated patients have been reported with the same missense GoF variant in ARAF (c.640T>C:p.S214P) who both had a complex lymphatic anomaly (no haplotype analysis was done). Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions. A zebrafish model recapitulated the lymphatic phenotype. The cellular, zebrafish and patient clinical phenotypes were all rescued with with a MEK inhibitor.
Segmental overgrowth disorders - Deep sequencing v3.6 ARAF Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: ARAF.
Segmental overgrowth disorders - Deep sequencing v3.6 ARAF Arina Puzriakova Entity copied from Mosaic skin disorders - deep sequencing v2.2
Segmental overgrowth disorders - Deep sequencing v3.6 ARAF Arina Puzriakova gene: ARAF was added
gene: ARAF was added to Segmental overgrowth disorders - Deep sequencing. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: ARAF 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: ARAF were set to 31263281
Phenotypes for gene: ARAF were set to central conducting lymphatic anomaly
Penetrance for gene: ARAF were set to unknown
Mode of pathogenicity for gene: ARAF was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mosaic skin disorders - deep sequencing v2.2 ARAF Arina Puzriakova Classified gene: ARAF as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.2 ARAF Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). ARAF is not currently associated with any phenotype in OMIM or G2P. Although only two patients have been reported with the same missense variant, functional studies including an animal model provide strong support of pathogenicity (outlined below). Evidence of this variant specific gene-disease relationship is sufficiently compelling but the phenotype is more within scope of the R110 Segmental overgrowth disorders – Deep sequencing panel. Therefore rating as amber on this panel and green on R110.

- PMID: 31263281 (2019):
To date, only two unrelated patients have been reported with the same missense GoF variant in ARAF (c.640T>C:p.S214P) who both had a complex lymphatic anomaly (no haplotype analysis was done). Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions. A zebrafish model recapitulated the lymphatic phenotype. The cellular, zebrafish and patient clinical phenotypes were all rescued with with a MEK inhibitor.
Mosaic skin disorders - deep sequencing v2.2 ARAF Arina Puzriakova Gene: araf has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: DAGLA.
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Phenotypes for gene: DAGLA were changed from intellectual disability, MONDO:0001071 to intellectual disability, MONDO:0001071
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Phenotypes for gene: DAGLA were changed from intellectual disability, MONDO:0001071 to intellectual disability, MONDO:0001071
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Phenotypes for gene: DAGLA were changed from intellectual disability, MONDO:0001071 to intellectual disability, MONDO:0001071
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Phenotypes for gene: DAGLA were changed from intellectual disability, MONDO:0001071 to intellectual disability, MONDO:0001071
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Phenotypes for gene: DAGLA were changed from intellectual disability, MONDO:0001071 to intellectual disability, MONDO:0001071
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Phenotypes for gene: DAGLA were changed from intellectual disability, MONDO:0001071 to intellectual disability, MONDO:0001071
Intellectual disability v5.209 DAGLA Achchuthan Shanmugasundram Phenotypes for gene: DAGLA were changed from developmental delay; ataxia; complex oculomotor abnormality to intellectual disability, MONDO:0001071
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Classified gene: DAGLA as Amber List (moderate evidence)
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Gene: dagla has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Classified gene: DAGLA as Amber List (moderate evidence)
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Gene: dagla has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Classified gene: DAGLA as Amber List (moderate evidence)
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Gene: dagla has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Classified gene: DAGLA as Amber List (moderate evidence)
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.208 DAGLA Achchuthan Shanmugasundram Gene: dagla has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Classified gene: DAGLA as Amber List (moderate evidence)
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Gene: dagla has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Classified gene: DAGLA as Amber List (moderate evidence)
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Gene: dagla has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Classified gene: DAGLA as Amber List (moderate evidence)
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Added comment: Comment on list classification: There are more than 3 unrelated cases associating monoallelic variants in this gene to intellectual disability. Hence, this gene can be promoted to Green rating at the next GMS update.
Intellectual disability v5.207 DAGLA Achchuthan Shanmugasundram Gene: dagla has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.206 DAGLA Achchuthan Shanmugasundram Publications for gene: DAGLA were set to 35737950
Intellectual disability v5.206 DAGLA Achchuthan Shanmugasundram Publications for gene: DAGLA were set to PMID: 35737950
Intellectual disability v5.205 DAGLA Achchuthan Shanmugasundram changed review comment from: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ (PMID:35737950).; to: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ. In addition, the functional data suggests potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect (PMID:35737950).
Intellectual disability v5.205 DAGLA Achchuthan Shanmugasundram changed review comment from: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ (PMID:35737950).; to: As reviewed by Irina Ziravecka, there are nine children from eight unrelated families reported with heterozygous de novo variants in DAGLA gene and presenting with a neuro-ocular phenotype characterized by developmental delay, ataxia and complex oculomotor abnormality. Of these nine children, five had intellectual disability and one had low average IQ (PMID:35737950).
Intellectual disability v5.205 DAGLA Achchuthan Shanmugasundram reviewed gene: DAGLA: Rating: GREEN; Mode of pathogenicity: None; Publications: 35737950; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v4.12 PYGM Siying Lin gene: PYGM was added
gene: PYGM was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: PYGM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PYGM were set to PMID 30316539
Phenotypes for gene: PYGM were set to Macular dystrophy, retinopathy
Mode of pathogenicity for gene: PYGM was set to Other
Review for gene: PYGM was set to GREEN
Added comment: Mahroo et al (PMID 30316539) report on 4 individuals with McArdle disease and biallelic variants in PYGM and similar retinopathy affecting the macula. Screening results for mutations in a number of macular dystrophy genes were negative, supporting the association of this retinopathy with McArdle disease
Sources: Literature
Hereditary ataxia with onset in adulthood v4.15 TDP1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: TDP1.
Hereditary ataxia with onset in adulthood v4.15 TDP1 Achchuthan Shanmugasundram edited their review of gene: TDP1: Changed rating: GREEN
Hereditary ataxia with onset in adulthood v4.15 TDP1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene can now be promoted to AMBER as there are three unrelated cases. The "founder-effect" tag has been added as they are all of Middle Eastern descent and harboured the same homozygous variant. However, the additional patient reported by Ian Berry (Leeds Genetics Laboratory) had the same variant in compound heterozygous state with another novel variant. Hence, this gene can be considered for promotion to GREEN rating at the next major review.; to: Comment on list classification: This gene can now be promoted to AMBER as there are three unrelated cases. The "founder-effect" tag has been added as they are all of Middle Eastern descent and harboured the same homozygous variant. However, the additional patient reported by Ian Berry (Leeds Genetics Laboratory) had the same variant in compound heterozygous state with another novel variant. As there is an additional variant reported, this gene can be considered for promotion to GREEN rating at the next major review.
Hereditary ataxia with onset in adulthood v4.15 TDP1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene can now be promoted to AMBER as there are three unrelated cases. The "founder-effect" tag has been added as they are all of Middle Eastern descent and harboured the same homozygous variant. Hence, it cannot be promoted to green rating.; to: Comment on list classification: This gene can now be promoted to AMBER as there are three unrelated cases. The "founder-effect" tag has been added as they are all of Middle Eastern descent and harboured the same homozygous variant. However, the additional patient reported by Ian Berry (Leeds Genetics Laboratory) had the same variant in compound heterozygous state with another novel variant. Hence, this gene can be considered for promotion to GREEN rating at the next major review.
Paroxysmal central nervous system disorders v3.1 RHOBTB2 Dmitrijs Rots reviewed gene: RHOBTB2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Clefting v4.80 AMOTL1 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: AMOTL1.
Clefting v4.80 AMOTL1 Arina Puzriakova Publications for gene: AMOTL1 were set to 33026150; 30375152
Clefting v4.79 AMOTL1 Arina Puzriakova Classified gene: AMOTL1 as Amber List (moderate evidence)
Clefting v4.79 AMOTL1 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to rate this gene as Green at the next GMS panel update.

At least 16 individuals from 12 families have been identified with heterozygous variants in a AMOTL1 hotspot (PMIDs: 30375152; 33026150; 36751037). The most common clinical features were orofacial clefting (15/16; 94%), large and dysplastic ears (10/16; 62.5%), congenital heart disease (8/16; 50%), tall stature (7/16; 44%), hearing loss (5/16; 31%), liver disease (5/16; 31%), and neurodevelopmental disease (5/16; 31%).
Clefting v4.79 AMOTL1 Arina Puzriakova Gene: amotl1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.170 MASP1 Achchuthan Shanmugasundram reviewed gene: MASP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33765348, 36980886; Phenotypes: 3MC syndrome 1, OMIM:257920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v3.90 ACAN Arina Puzriakova commented on gene: ACAN
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.170 KANSL1 Achchuthan Shanmugasundram reviewed gene: KANSL1: Rating: RED; Mode of pathogenicity: None; Publications: 26424144, 29093661, 36980886; Phenotypes: craniosynostosis, MONDO:0015469; Mode of inheritance: None
Childhood solid tumours v4.5 FBXW7 Arina Puzriakova Classified gene: FBXW7 as Amber List (moderate evidence)
Childhood solid tumours v4.5 FBXW7 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as at present I do not think there is enough evidence to classify this as a diagnostic-grade cancer gene.

There are previous reports of dn/inh germline variants in individuals (likely 7) with tumor predisposition, two had structural alternations that affected other genomic regions and the others were identified from a targeted Wilms cohort.
FBXW7 heterozygous variants have also been associated with a neurodevelopmental disorder (OMIM:620012; G2P - moderate) but these individuals not shown malignancy. FBXW7 is not linked to a cancer phenotype in OMIM or G2P.
Nonetheless this is a tumour suppressor gene that is worth monitoring for new evidence linking to cancer susceptibility (added watchlist tag).
Childhood solid tumours v4.5 FBXW7 Arina Puzriakova Gene: fbxw7 has been classified as Amber List (Moderate Evidence).
Childhood solid tumours v4.4 FBXW7 Arina Puzriakova Phenotypes for gene: FBXW7 were changed from Developmental delay, hypotonia, and impaired language to Wilms tumor, MONDO:0006058; Rhabdoid tumor, MONDO:0002728
Childhood solid tumours v4.3 FBXW7 Arina Puzriakova Publications for gene: FBXW7 were set to 30885698
Childhood solid tumours v4.2 FBXW7 Arina Puzriakova Tag watchlist tag was added to gene: FBXW7.
Childhood solid tumours v4.2 FBXW7 Arina Puzriakova reviewed gene: FBXW7: Rating: ; Mode of pathogenicity: None; Publications: 19963109, 20332316, 26482194, 30885698; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Breast cancer pertinent cancer susceptibility v2.5 CDH1 Arina Puzriakova Publications for gene: CDH1 were set to 36436516
Breast cancer pertinent cancer susceptibility v2.4 CDH1 Arina Puzriakova Phenotypes for gene: CDH1 were changed from Lobular breast cancer to Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, OMIM:137215
Breast cancer pertinent cancer susceptibility v2.3 CDH1 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: CDH1.
Tag Q3_23_expert_review tag was added to gene: CDH1.
Breast cancer pertinent cancer susceptibility v2.3 CDH1 Arina Puzriakova Classified gene: CDH1 as Amber List (moderate evidence)
Breast cancer pertinent cancer susceptibility v2.3 CDH1 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane. Germline heterozygous variants have been found in diffuse gastric and lobular breast cancer syndrome. Patients may develop lobular breast cancer only or lobular breast cancer with gastric cancer. Lobular carcinoma of the breast has been reported in up to 60% of female carriers.

Overall there is sufficient evidence to classify this as a breast cancer susceptibility gene. However, it should be noted that this gene is already covered by a targeted panel, R215 CDH1-related cancer syndrome. Will leave the decision with the GMS expert group as to whether this phenotype should also be covered by this panel.
Breast cancer pertinent cancer susceptibility v2.3 CDH1 Arina Puzriakova Gene: cdh1 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.170 SCARF2 Achchuthan Shanmugasundram reviewed gene: SCARF2: Rating: RED; Mode of pathogenicity: None; Publications: 29168297, 29620724, 36980886; Phenotypes: Van den Ende-Gupta syndrome, OMIM:600920, craniosynostosis, MONDO:0015469; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.170 ZCCHC11 Achchuthan Shanmugasundram gene: ZCCHC11 was added
gene: ZCCHC11 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ZCCHC11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZCCHC11 were set to 28808027; 36980886
Phenotypes for gene: ZCCHC11 were set to craniosynostosis, MONDO:0015469
Review for gene: ZCCHC11 was set to RED
Added comment: An individual was described with metopic synostosis and a novel de novo frameshift variant in ZCCHC11 (p.Glu1275fs) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.169 ZBTB20 Achchuthan Shanmugasundram gene: ZBTB20 was added
gene: ZBTB20 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ZBTB20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB20 were set to 34429528; 36980886
Phenotypes for gene: ZBTB20 were set to Primrose syndrome, OMIM:259050; craniosynostosis, MONDO:0015469
Review for gene: ZBTB20 was set to RED
Added comment: A de novo missense variant (c.1948A>C; p.Asn650His) was identified in an individual from the 100k genomes project with craniosynostosis, congenital heart disease, intellectual disability, and spinal anomalies (PMID:34429528).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.168 TWIST2 Achchuthan Shanmugasundram Publications for gene: TWIST2 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.167 TWIST2 Achchuthan Shanmugasundram Mode of inheritance for gene: TWIST2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.166 TWIST2 Achchuthan Shanmugasundram reviewed gene: TWIST2: Rating: RED; Mode of pathogenicity: None; Publications: 31292255, 36980886; Phenotypes: craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.166 TMEM251 Achchuthan Shanmugasundram gene: TMEM251 was added
gene: TMEM251 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: TMEM251 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM251 were set to 33252156; 36980886
Phenotypes for gene: TMEM251 were set to Dysostosis multiplex, Ain-Naz type, OMIM:619345; craniosynostosis, MONDO:0015469
Review for gene: TMEM251 was set to RED
Added comment: Whole-exome sequencing identified two homozygous variants c.133C>T/ p.Arg45Trp (absent from gnomAD) and c.215dupA/ p.Tyr72Ter (2 alleles in gnomAD, annotated as pathogenic in ClinVar), in two families. Immunofluorescence and confocal studies show that the p.Arg45Trp mutant TMEM251 protein was targeted less efficiently to the Golgi complex compared to wildtype protein (PMID:33252156).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.165 SRCAP Achchuthan Shanmugasundram gene: SRCAP was added
gene: SRCAP was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SRCAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRCAP were set to 33288889; 36980886
Review for gene: SRCAP was set to RED
Added comment: One individual was described with a stop-gain variant in SRCAP (c.7303C>T; p.Arg2435Ter) in the Norwegian cohort (PMID:33288889).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.164 SPRY4 Achchuthan Shanmugasundram gene: SPRY4 was added
gene: SPRY4 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SPRY4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPRY4 were set to 28808027; 36980886
Phenotypes for gene: SPRY4 were set to craniosynostosis, MONDO:0015469
Review for gene: SPRY4 was set to RED
Added comment: An individual was described with a heterozygous de novo variant in SPRY4 (p.Glu160Ter) (PMID:28808027). This gene has a low pLI (0) suggesting tolerance to loss-of-function.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.163 SP7 Achchuthan Shanmugasundram gene: SP7 was added
gene: SP7 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SP7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SP7 were set to 35121733; 36980886
Phenotypes for gene: SP7 were set to craniosynostosis, MONDO:0015469
Review for gene: SP7 was set to RED
Added comment: A de novo missense variant (c.926 C>G; p.Ser309Trp) in SP7 was identified in a patient with craniosynostosis, cranial hyperostosis, and long bone fragility. Mice with the corresponding variant also show a complex skeletal phenotype distinct from that of Sp7-null mice (PMID:35121733).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.162 SMURF1 Achchuthan Shanmugasundram changed review comment from: An individual was described with metopic synostosis and a de novo variant in SMURF1 (p.Arg468Trp) (PMID:28808027)
Sources: Literature; to: An individual was described with metopic synostosis and a de novo variant in SMURF1 (p.Arg468Trp) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.162 SMURF1 Achchuthan Shanmugasundram gene: SMURF1 was added
gene: SMURF1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SMURF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SMURF1 were set to 28808027; 36980886
Phenotypes for gene: SMURF1 were set to craniosynostosis, MONDO:0015469
Review for gene: SMURF1 was set to RED
Added comment: An individual was described with metopic synostosis and a de novo variant in SMURF1 (p.Arg468Trp) (PMID:28808027)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.161 SMC1A Achchuthan Shanmugasundram gene: SMC1A was added
gene: SMC1A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SMC1A 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: SMC1A were set to 29037998; 36980886
Phenotypes for gene: SMC1A were set to Cornelia de Lange syndrome 2, OMIM:300590; craniosynostosis, MONDO:0015469
Review for gene: SMC1A was set to RED
Added comment: An X-linked dominant variant (c.3581A>G; p.Tyr1194Cys) was identified in an individual with Cornelia de Lange syndrome (characterised by dysmorphic facial features, growth, and developmental delay and syndromic craniosynostosis). Their mother was mosaic for the variant (PMID:29037998).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.160 SMARCD2 Achchuthan Shanmugasundram gene: SMARCD2 was added
gene: SMARCD2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SMARCD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SMARCD2 were set to 28808027; 36980886
Phenotypes for gene: SMARCD2 were set to craniosynostosis, MONDO:0015469
Review for gene: SMARCD2 was set to RED
Added comment: An individual was described with metopic synostosis and a de novo variant in SMARCD2 (p.Arg73Ter) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.159 SMAD2 Achchuthan Shanmugasundram gene: SMAD2 was added
gene: SMAD2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SMAD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD2 were set to 34429528; 36980886
Phenotypes for gene: SMAD2 were set to Loeys-Dietz syndrome 6, OMIM:619656
Review for gene: SMAD2 was set to RED
Added comment: A de novo variant in SMAD2 (c.1223T>C; p.Leu408Pro) was identified in an individual within the craniosynostosis cohort of the 100k genomes project. The variant was absent from gnomAD and was predicted to affect a residue within a functional domain (PMID:34429528).
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.22 EZR Boaz Palterer gene: EZR was added
gene: EZR was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: EZR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EZR were set to 37301410
Phenotypes for gene: EZR were set to hypogammaglobulinemia; immunodeficiency
Penetrance for gene: EZR were set to unknown
Review for gene: EZR was set to RED
Added comment: One kindred with 1 affected subject (homozygous EZR p.A129T), disease segregates with the variant. Extensive functional analysis.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.158 SIX2 Achchuthan Shanmugasundram gene: SIX2 was added
gene: SIX2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SIX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIX2 were set to 26581443; 36980886
Phenotypes for gene: SIX2 were set to six2-related frontonasal dysplasia, MONDO:0044628; craniosynostosis, MONDO:0015469
Review for gene: SIX2 was set to RED
Added comment: A family with a dominantly inherited craniofacial phenotype (frontal bossing with high hairline, ptosis, hypertelorism, broad nasal tip, large anterior fontanelle, cranial base anomalies, and sagittal synostosis (only confirmed in one individual)) were identified on chromosomal microarray to harbour a heterozygous 108.3 kilobase deletion of chromosome 2p21 (disrupting SIX2 and the surround non-coding DNA) (PMID:26581443).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.157 SH3BP4 Achchuthan Shanmugasundram gene: SH3BP4 was added
gene: SH3BP4 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SH3BP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SH3BP4 were set to 35080095; 36980886
Phenotypes for gene: SH3BP4 were set to craniosynostosis, MONDO:0015469
Review for gene: SH3BP4 was set to RED
Added comment: A patient was described with a recessive variant in SH3BP4 (c.128C>A; p.Pro43His) in the Norwegian craniosynostosis cohort. The variant has a CADD score of 33 and a gnomAD allele frequency of 9.6 x 10-5 (no homozygotes are reported in gnomAD). The patient presented with a Chiari I malformation, exophthalmos, eating difficulties as an infant, microcephaly, recurrent infections, dysmorphic features, Kabuki-like syndrome, and pan-synostosis. This patient also harbours two variants in KMT2D: c.11599C>A; p.Gln3867Lys (CADD = 22) and c.7182C>A; p.Ser2394Arg (CADD = 20); gnomAD frequency 1.2 x 10-5 and absent, respectively (PMID:35080095).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.156 SCN8A Achchuthan Shanmugasundram changed review comment from: A heterozygous duplication involving SCN8A was identified in an individual with hearing impairment, hypermobility, intellectual disability, ventricular septal defect and craniosynostosis (c.3924dup; p.Arg1309Thrfs*3) (PMID:34429528)
Sources: Literature; to: A heterozygous duplication involving SCN8A was identified in an individual with hearing impairment, hypermobility, intellectual disability, ventricular septal defect and craniosynostosis (c.3924dup; p.Arg1309Thrfs*3) (PMID:34429528).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.156 SCN8A Achchuthan Shanmugasundram gene: SCN8A was added
gene: SCN8A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: SCN8A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCN8A were set to 34429528; 36980886
Phenotypes for gene: SCN8A were set to craniosynostosis, MONDO:0015469
Review for gene: SCN8A was set to RED
Added comment: A heterozygous duplication involving SCN8A was identified in an individual with hearing impairment, hypermobility, intellectual disability, ventricular septal defect and craniosynostosis (c.3924dup; p.Arg1309Thrfs*3) (PMID:34429528)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.155 RASAL2 Achchuthan Shanmugasundram gene: RASAL2 was added
gene: RASAL2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: RASAL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RASAL2 were set to 28808027; 36980886
Phenotypes for gene: RASAL2 were set to craniosynostosis, MONDO:0015469
Review for gene: RASAL2 was set to RED
Added comment: An individual was described with sagittal synostosis and a de novo variant in RASAL2 (p.Arg571Pro) (PMID:28808027)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.154 PUF60 Achchuthan Shanmugasundram gene: PUF60 was added
gene: PUF60 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PUF60 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PUF60 were set to 36367278; 36980886
Phenotypes for gene: PUF60 were set to craniosynostosis, MONDO:0015469
Review for gene: PUF60 was set to RED
Added comment: A patient presenting with Verheij syndrome, characterised by craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay, was identified with a heterozygous variant in the splicing factor PUF60 (c.436C>T; p.Arg146Cys). They displayed fusion of the coronal and sagittal suture (PMID:36367278).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.153 PTH2R Achchuthan Shanmugasundram gene: PTH2R was added
gene: PTH2R was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PTH2R was set to Other
Publications for gene: PTH2R were set to 26044810; 36980886
Phenotypes for gene: PTH2R were set to craniosynostosis, MONDO:0015469
Review for gene: PTH2R was set to RED
Added comment: A boy presenting with sagittal and metopic synostosis was found to harbour a complex paracentric inversion involving 2q14.3 and 2q3. An intronic break of the PTH2R gene was
detected by whole genome sequencing and fluorescence in situ hybridisation (PMID:26044810).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.152 PSMD12 Achchuthan Shanmugasundram gene: PSMD12 was added
gene: PSMD12 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PSMD12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PSMD12 were set to 34429528; 36980886
Phenotypes for gene: PSMD12 were set to craniosynostosis, MONDO:0015469
Review for gene: PSMD12 was set to RED
Added comment: A heterozygous variant was identified in the UK 100k genomes project (parents were not available for testing): c.1284G>A; p.Trp428* (PMID:34429528)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.151 PSMC5 Achchuthan Shanmugasundram gene: PSMC5 was added
gene: PSMC5 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PSMC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC5 were set to 28808027; 36980886
Phenotypes for gene: PSMC5 were set to craniosynostosis, MONDO:0015469
Review for gene: PSMC5 was set to RED
Added comment: An individual was described with metopic synostosis and a de novo variant in PSMC5 (p.Arg317Trp) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.150 PSMC2 Achchuthan Shanmugasundram gene: PSMC2 was added
gene: PSMC2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PSMC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PSMC2 were set to 28808027; 36980886
Phenotypes for gene: PSMC2 were set to craniosynostosis, MONDO:0015469
Review for gene: PSMC2 was set to RED
Added comment: An individual was described with metopic synostosis and a de novo variant in PSMC2 (p.Arg297Gly) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.149 POLR2A Achchuthan Shanmugasundram gene: POLR2A was added
gene: POLR2A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: POLR2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR2A were set to 35080095; 36980886
Phenotypes for gene: POLR2A were set to Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, OMIM:618603; craniosynostosis, MONDO:0015469
Review for gene: POLR2A was set to RED
Added comment: A de novo insertion was identified in the Norwegian sequencing study: c.4329_4330delinsAA; p.Ala1444Thr. The variant is absent from gnomAD (v.2.1.1) but is not predicted to affect a functional domain. The patient displayed metopic synostosis, impaired motor skills, hypospadias, hypermobile joints and hyperactive behaviour (PMID:35080095).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.148 PITX2 Achchuthan Shanmugasundram gene: PITX2 was added
gene: PITX2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: PITX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PITX2 were set to 36980886
Review for gene: PITX2 was set to RED
Added comment: Tooze et al has reviewed in PMID:36980886 from unpublished data that two cases of de novo missense variants are known with craniosynostosis, but not reported.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.147 OSTM1 Achchuthan Shanmugasundram Phenotypes for gene: OSTM1 were changed from AR osteopetrosis 5 to Osteopetrosis, autosomal recessive 5, OMIM:259720; craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.146 OSTM1 Achchuthan Shanmugasundram Publications for gene: OSTM1 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.145 OSTM1 Achchuthan Shanmugasundram Mode of inheritance for gene: OSTM1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.144 OSTM1 Achchuthan Shanmugasundram edited their review of gene: OSTM1: Changed phenotypes to: Osteopetrosis, autosomal recessive 5, OMIM:259720, craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.144 OSTM1 Achchuthan Shanmugasundram changed review comment from: An individual was reported with osteopetrosis, craniosynostosis, and Chiari malformation type 1 and two novel homozygous variants in OSTEM1. The first was a missense variant c.265T>A (p.Val122Asp), which was considered neutral. The second variant was a synonymous change (c.108C>T) but was predicted to create a new donor splice site and disrupt mRNA processing (PMID:23772242).; to: An individual was reported with osteopetrosis, craniosynostosis, and Chiari malformation type 1 and two novel homozygous variants in OSTEM1. The first was a missense variant c.265T>A (p.Val122Asp), which was considered neutral. The second variant was a synonymous change (c.108C>T) but was predicted to create a new donor splice site and disrupt mRNA processing (PMID:23772242).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.144 OSTM1 Achchuthan Shanmugasundram reviewed gene: OSTM1: Rating: RED; Mode of pathogenicity: None; Publications: 23772242, 36980886; Phenotypes: craniosynostosis, MONDO:0015469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.144 NTRK2 Achchuthan Shanmugasundram gene: NTRK2 was added
gene: NTRK2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: NTRK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NTRK2 were set to 27884935; 36980886
Phenotypes for gene: NTRK2 were set to Obesity, hyperphagia, and developmental delay, OMIM:613886; craniosynostosis, MONDO:0015469
Review for gene: NTRK2 was set to RED
Added comment: A heterozygous stop-gain variant was identified in an individual with unicoronal synostosis, language delay, hyperphagic obesity, and aggression (c.1330G>T; p.Gly444*). It was suspected that the variant arose de novo but the father’s sample was not available for testing (PMID:27884935).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.143 NAA25 Achchuthan Shanmugasundram gene: NAA25 was added
gene: NAA25 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: NAA25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NAA25 were set to 30152016; 36980886
Phenotypes for gene: NAA25 were set to craniosynostosis, MONDO:0015469
Review for gene: NAA25 was set to RED
Added comment: One individual was described with sagittal synostosis to harbour a de novo frameshifting variant in NAA25 (p.Phe359fs*) (PMID:30152016).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.142 MMP21 Achchuthan Shanmugasundram gene: MMP21 was added
gene: MMP21 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: MMP21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMP21 were set to 34429528; 36980886
Phenotypes for gene: MMP21 were set to craniosynostosis, MONDO:0015469
Review for gene: MMP21 was set to RED
Added comment: Compound heterozygous variants (c.671_684del/ p.Val224Glyfs*29 and c.775C>G/ p.His259Asp) were identified in an individual within the 100kGP with heterotaxy and craniosynostosis (PMID:34429528)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.141 MED13L Achchuthan Shanmugasundram gene: MED13L was added
gene: MED13L was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: MED13L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MED13L were set to 28371282; 36980886
Phenotypes for gene: MED13L were set to Impaired intellectual development and distinctive facial features with or without cardiac defects, OMIM:616789; craniosynostosis, MONDO:0015469
Review for gene: MED13L was set to RED
Added comment: Two siblings exhibited an intragenic deletion of exons 3-14 resulting in MED13L haploinsufficiency syndrome (intellectual disability, developmental delay, heart defects and dysmorphic features). The deletion was inherited from their mother who showed low frequency mosaicism. The older sibling also presented with craniosynostosis (PMID:28371282).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.140 MACF1 Achchuthan Shanmugasundram gene: MACF1 was added
gene: MACF1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: MACF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MACF1 were set to 28808027; 36980886
Phenotypes for gene: MACF1 were set to craniosynostosis, MONDO:0015469
Review for gene: MACF1 was set to RED
Added comment: An individual was described with sagittal synostosis and a novel splicing variant in MACF1 (IVS89+1G>A) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.139 KPTN Achchuthan Shanmugasundram Classified gene: KPTN as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.139 KPTN Achchuthan Shanmugasundram Gene: kptn has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.138 KPTN Achchuthan Shanmugasundram gene: KPTN was added
gene: KPTN was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: KPTN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KPTN were set to 24239382; 36980886
Phenotypes for gene: KPTN were set to Intellectual developmental disorder, autosomal recessive 41, OMIM:615637; craniosynostosis, MONDO:0015469
Review for gene: KPTN was set to AMBER
Added comment: Four families were described with variants in KPTN and suspected craniosynostosis. Sagittal synostosis was confirmed in one individual from a family with three affected individuals. All families harboured a variant encoding p.Ser259*; this was homozygous in four individuals and in trans with another heterozygous variant (p.Met241_Gln246dup) in five individuals (PMID:24239382).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.137 KMT5B Achchuthan Shanmugasundram gene: KMT5B was added
gene: KMT5B was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: KMT5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KMT5B were set to 34429528; 36980886
Phenotypes for gene: KMT5B were set to craniosynostosis, MONDO:0015469
Review for gene: KMT5B was set to RED
Added comment: A de novo loss of function variant was identified within the 100kGP craniosynostosis cohort: c.557T>A; p.Leu186* (PMID:34429528).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.136 IFRD1 Achchuthan Shanmugasundram gene: IFRD1 was added
gene: IFRD1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: IFRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IFRD1 were set to 35997807; 36980886
Phenotypes for gene: IFRD1 were set to craniosynostosis, MONDO:0015469
Review for gene: IFRD1 was set to RED
Added comment: A de novo variant was identified in a cohort of patients with lambdoid synostosis (p.Gly6fs*) (PMID:35997807).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.135 HIST1H1E Achchuthan Shanmugasundram gene: HIST1H1E was added
gene: HIST1H1E was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
new-gene-name tags were added to gene: HIST1H1E.
Mode of inheritance for gene: HIST1H1E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H1E were set to 36118902; 36980886
Phenotypes for gene: HIST1H1E were set to craniosynostosis, MONDO:0015469
Review for gene: HIST1H1E was set to RED
Added comment: A patient with syndromic unilambdoid synostosis was found to harbour a frameshifting variant in HIST1H1E (c.433_434insC; p.Thr146Hisfs*50). The variant is reported as pathogenic for Rahman syndrome in ClinVar and absent from gnomAD (PMID:36118902).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.134 HDAC4 Achchuthan Shanmugasundram gene: HDAC4 was added
gene: HDAC4 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
cnv tags were added to gene: HDAC4.
Mode of inheritance for gene: HDAC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HDAC4 were set to 33288889; 36980886
Phenotypes for gene: HDAC4 were set to craniosynostosis, MONDO:0015469
Review for gene: HDAC4 was set to RED
Added comment: A patient was described with two copy number variants: g.233110452_ 243028452 and del g.210300_ 8664358dup. The second variant was maternally inherited (PMID:33288889)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.133 H3F3B Achchuthan Shanmugasundram gene: H3F3B was added
gene: H3F3B was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: H3F3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: H3F3B were set to 33268356; 36980886
Phenotypes for gene: H3F3B were set to craniosynostosis, MONDO:0015469
Review for gene: H3F3B was set to RED
Added comment: In a cohort of 33 patients with H3F3A variants and 13 patients with H3F3B variants, 5/13 (~40%) individuals with H3F3B variants were reported with “craniosynostosis or abnormal head shape”. Of these, it is not clear if these were radiologically confirmed and what proportion of this subset of patients had synostosis compared to dysmorphic features (PMID:33268356).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.132 H3F3A Achchuthan Shanmugasundram gene: H3F3A was added
gene: H3F3A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: H3F3A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: H3F3A were set to 33268356; 36980886
Phenotypes for gene: H3F3A were set to craniosynostosis, MONDO:0015469
Review for gene: H3F3A was set to RED
Added comment: In a cohort of 33 patients with H3F3A variants and 13 patients with H3F3B variants, 9/33 (~30%) individuals with H3F3A variants were reported with “craniosynostosis or abnormal head shape”. Of these, it is not clear if these were radiologically confirmed and what proportion of this subset of patients had synostosis compared to dysmorphic features (PMID:33268356).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.131 GLIS3 Achchuthan Shanmugasundram gene: GLIS3 was added
gene: GLIS3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: GLIS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLIS3 were set to 26259131; 36980886
Phenotypes for gene: GLIS3 were set to craniosynostosis, MONDO:0015469
Review for gene: GLIS3 was set to RED
Added comment: One patient was described with a variant in GLIS3 and sagittal craniosynostosis requiring surgical intervention. The patient harboured a homozygous deletion of exons 9 – 11; consanguinity was not confirmed but suspected (PMID:26259131).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.130 GPC4 Achchuthan Shanmugasundram gene: GPC4 was added
gene: GPC4 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: GPC4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GPC4 were set to 31292255; 36980886
Phenotypes for gene: GPC4 were set to craniosynostosis, MONDO:0015469
Review for gene: GPC4 was set to RED
Added comment: A variant in GPC4 was identified in an individual with syndromic craniosynostosis. The variant encoding p.Val152fs arose de novo in the mother (PMID:31292255)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.129 GLI2 Achchuthan Shanmugasundram gene: GLI2 was added
gene: GLI2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: GLI2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GLI2 were set to 31292255; 36980886
Phenotypes for gene: GLI2 were set to craniosynostosis, MONDO:0015469
Review for gene: GLI2 was set to RED
Added comment: A de novo GLI2 variant (p.Ala551Thr) was identified in an individual with syndromic craniosynostosis (PMID:31292255).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.128 FUZ Achchuthan Shanmugasundram gene: FUZ was added
gene: FUZ was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: FUZ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUZ were set to 34719684; 36980886
Phenotypes for gene: FUZ were set to craniosynostosis, MONDO:0015469
Review for gene: FUZ was set to RED
Added comment: A pair of monozygotic twins were described with craniosynostosis and a novel variant in FUZ (c.851G>C; p.Arg284Pro) (PMID:34719684).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.127 FTO Achchuthan Shanmugasundram gene: FTO was added
gene: FTO was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: FTO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FTO were set to 26697951; 36980886
Phenotypes for gene: FTO were set to craniosynostosis, MONDO:0015469
Review for gene: FTO was set to RED
Added comment: A homozygous variant in FTO (c.956G>A; p.Arg322Gln) was described in one individual with multiple malformation syndrome, which included craniosynostosis. Craniosynostosis is not a consistent feature of variants in FTO (PMID:26697951).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.126 FOXO1 Achchuthan Shanmugasundram gene: FOXO1 was added
gene: FOXO1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: FOXO1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXO1 were set to 35997807; 36980886
Phenotypes for gene: FOXO1 were set to craniosynostosis, MONDO:0015469
Review for gene: FOXO1 was set to RED
Added comment: PMID:35997807 reported a cohort of patients with lambdoid synostosis, where a de novo variant (p.Arg180Trp) was identified in FOXO1. Hence, this gene should be added with a red rating.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.125 FOXP2 Achchuthan Shanmugasundram gene: FOXP2 was added
gene: FOXP2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: FOXP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXP2 were set to 35080095; 36980886
Phenotypes for gene: FOXP2 were set to craniosynostosis, MONDO:0015469
Review for gene: FOXP2 was set to RED
Added comment: A familial variant in FOXP2 (c.484del; p.Gln162fs) was identified in individuals with developmental delay, hypermetropia, orofacial dyspraxia and sagittal craniosynostosis. The variant is absent from gnomAD (PMID:35080095)
Sources: Literature
Paediatric disorders - additional genes v3.3 FOXL2 Arina Puzriakova commented on gene: FOXL2: Helen Brittain (Genomics England Clinical Team) supports inclusion of BPES and blepharophimosis genes on this panel as these are features that would be considered under the dysmorphism indication.
Limb disorders v4.7 ISCA-37467-Gain Arina Puzriakova changed review comment from: Comment on list classification: Adding to this panel under the suggestion of Helen Brittain (Genomics England Clinical Team) as this region is associated with limb malformation phenotypes. Enough evidence to rate this gene as Green at the next GMS panel update.; to: Comment on list classification: Adding to this panel under the suggestion of Helen Brittain (Genomics England Clinical Team) as this region is associated with limb malformation phenotypes. Enough evidence to rate as Green at the next GMS panel update.
Limb disorders v4.7 ISCA-37467-Gain Arina Puzriakova Tag Q3_23_promote_green tag was added to Region: ISCA-37467-Gain.
Limb disorders v4.7 ISCA-37467-Gain Arina Puzriakova Classified Region: ISCA-37467-Gain as Amber List (moderate evidence)
Limb disorders v4.7 ISCA-37467-Gain Arina Puzriakova Added comment: Comment on list classification: Adding to this panel under the suggestion of Helen Brittain (Genomics England Clinical Team) as this region is associated with limb malformation phenotypes. Enough evidence to rate this gene as Green at the next GMS panel update.
Limb disorders v4.7 ISCA-37467-Gain Arina Puzriakova Region: isca-37467-gain has been classified as Amber List (Moderate Evidence).
Limb disorders v4.6 ISCA-37467-Gain Arina Puzriakova Deleted their comment
Limb disorders v4.6 ISCA-37467-Gain Arina Puzriakova Entity copied from Clefting v4.78
Limb disorders v4.6 ISCA-37467-Gain Arina Puzriakova Region: ISCA-37467-Gain was added
Region: ISCA-37467-Gain was added to Limb disorders. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37467-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37467-Gain were set to 19291772; 18417549; 18178630
Phenotypes for Region: ISCA-37467-Gain were set to human triphalangeal thumb and polysyndactyly (TPT-PS) phenotype; 174500; Triphalangeal thumbpolysyndactyly syndrome; syndactyly type IV with tibial hypoplasia
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.124 FOXP1 Achchuthan Shanmugasundram gene: FOXP1 was added
gene: FOXP1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: FOXP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXP1 were set to 29330474; 36980886
Phenotypes for gene: FOXP1 were set to craniosynostosis, MONDO:0015469
Review for gene: FOXP1 was set to RED
Added comment: Whole exome sequencing identified a de novo splicing variant in FOXP1 (c.1428+1 G>A; p.Ala450GLyfs*13) in a patient with syndromic intellectual disability and trigonocephaly (PMID:29330474).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.123 EXTL3 Achchuthan Shanmugasundram changed review comment from: A recessive variant in EXTL3 (c.2392G>A; p.Val798Met) was identified in a patient with metopic craniosynostosis, intellectual disability, short stature, microcephaly, hip dysplasia, kyphosis, delayed skeletal age and immunodeficiency. The variant is absent from gnomAD and affects the glycosyl transferase family 64 domain (PMID:35080095).

Craniosynostosis has been recorded as part of the phenotype in OMIM (MIM #617425)
Sources: Literature; to: A recessive variant in EXTL3 (c.2392G>A; p.Val798Met) was identified in a patient with metopic craniosynostosis, intellectual disability, short stature, microcephaly, hip dysplasia, kyphosis, delayed skeletal age and immunodeficiency. The variant is absent from gnomAD and affects the glycosyl transferase family 64 domain (PMID:35080095).

Craniosynostosis has been recorded as part of the phenotype in OMIM (MIM #617425).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.123 EXTL3 Achchuthan Shanmugasundram changed review comment from: A recessive variant in EXTL3 (c.2392G>A; p.Val798Met) was identified in a patient with metopic craniosynostosis, intellectual disability, short stature, microcephaly, hip dysplasia, kyphosis, delayed skeletal age and immunodeficiency. The variant is absent from gnomAD and affects the glycosyl transferase family 64 domain (PMID:35080095).
Sources: Literature; to: A recessive variant in EXTL3 (c.2392G>A; p.Val798Met) was identified in a patient with metopic craniosynostosis, intellectual disability, short stature, microcephaly, hip dysplasia, kyphosis, delayed skeletal age and immunodeficiency. The variant is absent from gnomAD and affects the glycosyl transferase family 64 domain (PMID:35080095).

Craniosynostosis has been recorded as part of the phenotype in OMIM (MIM #617425)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.123 EXTL3 Achchuthan Shanmugasundram edited their review of gene: EXTL3: Changed phenotypes to: Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.123 EXTL3 Achchuthan Shanmugasundram Phenotypes for gene: EXTL3 were changed from craniosynostosis, MONDO:0015469 to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.122 EXTL3 Achchuthan Shanmugasundram gene: EXTL3 was added
gene: EXTL3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: EXTL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXTL3 were set to 35080095; 36980886
Phenotypes for gene: EXTL3 were set to craniosynostosis, MONDO:0015469
Review for gene: EXTL3 was set to RED
Added comment: A recessive variant in EXTL3 (c.2392G>A; p.Val798Met) was identified in a patient with metopic craniosynostosis, intellectual disability, short stature, microcephaly, hip dysplasia, kyphosis, delayed skeletal age and immunodeficiency. The variant is absent from gnomAD and affects the glycosyl transferase family 64 domain (PMID:35080095).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.121 EIF5A Achchuthan Shanmugasundram gene: EIF5A was added
gene: EIF5A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EIF5A were set to 36118902; 36980886
Phenotypes for gene: EIF5A were set to craniosynostosis, MONDO:0015469
Review for gene: EIF5A was set to RED
Added comment: An intronic variant was identified in EIF5A (c.271-1G>C) within the Chinese cohort in a patient with metopic synostosis (PMID:36118902).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.120 EHMT1 Achchuthan Shanmugasundram gene: EHMT1 was added
gene: EHMT1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: EHMT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EHMT1 were set to 33288889; 36980886
Phenotypes for gene: EHMT1 were set to craniosynostosis, MONDO:0015469
Review for gene: EHMT1 was set to RED
Added comment: A de novo splicing variant was identified in EHMT1 (c.2018+1G>C) within the Norwegian cohort with syndromic craniosynostosis (PMID:33288889).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.119 DVL3 Achchuthan Shanmugasundram gene: DVL3 was added
gene: DVL3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: DVL3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DVL3 were set to 28808027; 36980886
Phenotypes for gene: DVL3 were set to craniosynostosis, MONDO:0015469
Review for gene: DVL3 was set to RED
Added comment: An individual was described with sagittal synostosis and a de novo variant in DVL3 (p.Gly327fs*) (PMID:28808027).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.118 DDX3X Achchuthan Shanmugasundram changed review comment from: A novel de novo missense variant was identified in the DDX3X gene (c.625C>G) by whole exome sequencing in a child with craniofacial dysmorphisms: brachycephaly and a flattened triangular-asymmetrical face characterized by micrognathia, mild hypertelorism, wide and prominent nose, short philtrum, thin lips and macroglossia (PMID:33789733).

Exome-sequencing identified three distinct de novo heterozygous variants in DDX3X: c.1511G>A; p.(Gly504Glu) (Patient 1), c.1436_1439delinsTCTC; p.(Asp479Arg480delinsValSer) (Patient 2), and c.641_643delTCA; p.(Ile214del) (Patient 3). The patients showed severe intellectual disability/developmental disorders, microcephaly, and dysmorphic features. Plagiocephaly was observed in Patient 1 and Patient 2 was diagnosed with sensorineural hearing loss and trigonocephaly. However, craniosynostosis was only radiologically confirmed in Patient 2 (PMID:30936465).

A de novo variant in DDX3X was identified in an additional patient with trigonocephaly, delay in speech acquisition and motor developmental delay: c.1616-2A>G; p.(?) (PMID:32530565).
Sources: Literature; to: A novel de novo missense variant was identified in the DDX3X gene (c.625C>G) by whole exome sequencing in a child with craniofacial dysmorphisms: brachycephaly and a flattened triangular-asymmetrical face characterized by micrognathia, mild hypertelorism, wide and prominent nose, short philtrum, thin lips and macroglossia (PMID:33789733).

Exome-sequencing identified three distinct de novo heterozygous variants in DDX3X: c.1511G>A; p.(Gly504Glu) (Patient 1), c.1436_1439delinsTCTC; p.(Asp479Arg480delinsValSer) (Patient 2), and c.641_643delTCA; p.(Ile214del) (Patient 3). The patients showed severe intellectual disability/developmental disorders, microcephaly, and dysmorphic features. Plagiocephaly was observed in Patient 1 and Patient 2 was diagnosed with sensorineural hearing loss and trigonocephaly. However, craniosynostosis was only radiologically confirmed in Patient 2 (PMID:30936465).

A de novo variant in DDX3X was identified in an additional patient with trigonocephaly, delay in speech acquisition and motor developmental delay: c.1616-2A>G (PMID:32530565).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.118 DDX3X Achchuthan Shanmugasundram Classified gene: DDX3X as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.118 DDX3X Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are five unrelated cases reported with DDX3X variants and likely craniosynostosis, only two are radiologically confirmed cases of craniosynostosis. Hence, this gene should be rated amber.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.118 DDX3X Achchuthan Shanmugasundram Gene: ddx3x has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.117 DDX3X Achchuthan Shanmugasundram Phenotypes for gene: DDX3X were changed from craniosynostosis, MONDO:0015469 to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958; craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.116 DDX3X Achchuthan Shanmugasundram edited their review of gene: DDX3X: Changed phenotypes to: Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958, craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.116 DDX3X Achchuthan Shanmugasundram gene: DDX3X was added
gene: DDX3X was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: DDX3X 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: DDX3X were set to 30936465; 32530565; 33789733; 36980886
Phenotypes for gene: DDX3X were set to craniosynostosis, MONDO:0015469
Review for gene: DDX3X was set to AMBER
Added comment: A novel de novo missense variant was identified in the DDX3X gene (c.625C>G) by whole exome sequencing in a child with craniofacial dysmorphisms: brachycephaly and a flattened triangular-asymmetrical face characterized by micrognathia, mild hypertelorism, wide and prominent nose, short philtrum, thin lips and macroglossia (PMID:33789733).

Exome-sequencing identified three distinct de novo heterozygous variants in DDX3X: c.1511G>A; p.(Gly504Glu) (Patient 1), c.1436_1439delinsTCTC; p.(Asp479Arg480delinsValSer) (Patient 2), and c.641_643delTCA; p.(Ile214del) (Patient 3). The patients showed severe intellectual disability/developmental disorders, microcephaly, and dysmorphic features. Plagiocephaly was observed in Patient 1 and Patient 2 was diagnosed with sensorineural hearing loss and trigonocephaly. However, craniosynostosis was only radiologically confirmed in Patient 2 (PMID:30936465).

A de novo variant in DDX3X was identified in an additional patient with trigonocephaly, delay in speech acquisition and motor developmental delay: c.1616-2A>G; p.(?) (PMID:32530565).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.115 CTNNA1 Achchuthan Shanmugasundram gene: CTNNA1 was added
gene: CTNNA1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: CTNNA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTNNA1 were set to 31292255; 36980886
Phenotypes for gene: CTNNA1 were set to craniosynostosis, MONDO:0015469
Review for gene: CTNNA1 was set to RED
Added comment: A de novo insertion (p.Val374_375ins) was identified in an individual from a screen of patients with syndromic craniosynostosis. This patient had sagittal craniosynostosis (PMID:31292255).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.114 COL11A1 Achchuthan Shanmugasundram gene: COL11A1 was added
gene: COL11A1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: COL11A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COL11A1 were set to 34429528; 36980886
Phenotypes for gene: COL11A1 were set to craniosynostosis, MONDO:0015469
Review for gene: COL11A1 was set to RED
Added comment: A de novo loss of function variant (c.2852+5G>A) was identified in an individual with craniosynostosis and a hearing impairment from the UK 100k genomes project (PMID:34429528)
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.113 CHD3 Achchuthan Shanmugasundram gene: CHD3 was added
gene: CHD3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: CHD3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CHD3 were set to 30397230; 36980886
Phenotypes for gene: CHD3 were set to craniosynostosis, MONDO:0015469
Review for gene: CHD3 was set to RED
Added comment: One of 35 individuals identified with Snijders Blok Campeau syndrome (neurodevelopmental disorder, macrocephaly and impaired speech and language) and with monoallelic variants in CHD3 gene (c.3482A>G; p.His1161Arg) presented with sagittal synostosis (PMID:30397230).

In addition, one of 28 patients with sequence variants (c.52_53inv; p.Ser18Glu) in the DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes./
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.112 CDK8 Achchuthan Shanmugasundram gene: CDK8 was added
gene: CDK8 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: CDK8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDK8 were set to 30905399; 36980886
Phenotypes for gene: CDK8 were set to craniosynostosis, MONDO:0015469
Review for gene: CDK8 was set to RED
Added comment: Metopic synostosis was described in one individual out of 12 reported with variants in CDK8 from PMID:30905399. This individual harboured a de novo c.88G>A (p.Gly30Ser) variant.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.111 CACNA1E Achchuthan Shanmugasundram Phenotypes for gene: CACNA1E were changed from crannieynostosis, MONDO:0015469s to craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.110 CACNA1E Achchuthan Shanmugasundram edited their review of gene: CACNA1E: Changed phenotypes to: craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.110 CACNA1E Achchuthan Shanmugasundram gene: CACNA1E was added
gene: CACNA1E was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: CACNA1E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CACNA1E were set to 32530565; 36980886
Phenotypes for gene: CACNA1E were set to crannieynostosis, MONDO:0015469s
Review for gene: CACNA1E was set to RED
Added comment: A heterozygous splice variant (c.3674+5A>G) was identified in an individual from a cohort of patients with trigonocephaly (PMID:32530565).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.109 BRWD3 Achchuthan Shanmugasundram changed review comment from: A de novo stop-gain variant (p.Gln1338*) was identified in an individual with craniosynostosis within the 100k genomes project cohort (PMID:34429528). In addition, one of 20 patients with sequence variants in BRWD3 gene from DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes.
Sources: Literature; to: A de novo stop-gain variant (p.Gln1338*) was identified in an individual with craniosynostosis within the 100k genomes project cohort (PMID:34429528). In addition, one of 20 patients with sequence variants in BRWD3 gene (p.Gly707Val) from DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.109 BRWD3 Achchuthan Shanmugasundram Phenotypes for gene: BRWD3 were changed from to craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.108 BRWD3 Achchuthan Shanmugasundram edited their review of gene: BRWD3: Changed phenotypes to: craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.108 BRWD3 Achchuthan Shanmugasundram gene: BRWD3 was added
gene: BRWD3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: BRWD3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: BRWD3 were set to 34429528; 36980886
Review for gene: BRWD3 was set to RED
Added comment: A de novo stop-gain variant (p.Gln1338*) was identified in an individual with craniosynostosis within the 100k genomes project cohort (PMID:34429528). In addition, one of 20 patients with sequence variants in BRWD3 gene from DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes.
Sources: Literature
Nephrocalcinosis or nephrolithiasis v4.1 SLC26A1 Detlef Bockenhauer reviewed gene: SLC26A1: Rating: RED; Mode of pathogenicity: None; Publications: 36719378; Phenotypes: hyperoxaluria; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.107 AXIN1 Achchuthan Shanmugasundram gene: AXIN1 was added
gene: AXIN1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: AXIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AXIN1 were set to 28808027; 36980886
Phenotypes for gene: AXIN1 were set to craniosynostosis, MONDO:0015469
Review for gene: AXIN1 was set to RED
Added comment: PMID:28808027 reported an individual with sagittal synostosis and a de novo heterozygous variant in AXIN1 gene.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.106 ARAP3 Achchuthan Shanmugasundram gene: ARAP3 was added
gene: ARAP3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ARAP3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARAP3 were set to 28808027; 36980886
Phenotypes for gene: ARAP3 were set to craniosynostosis, MONDO:0015469
Review for gene: ARAP3 was set to RED
Added comment: PMID:28808027 reported an individual identified with a de novo variant in ARAP3 (IVS6+1delGT) and presenting with metopic synostosis. As there is only one case reported so far, this gene should be rated red.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.105 ANKH Achchuthan Shanmugasundram Classified gene: ANKH as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.105 ANKH Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two cases reported in total with craniosynostosis. Hence, this gene can be rated amber.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.105 ANKH Achchuthan Shanmugasundram Gene: ankh has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.104 ANKH Achchuthan Shanmugasundram gene: ANKH was added
gene: ANKH was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ANKH was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ANKH were set to 36118902; 36980886
Phenotypes for gene: ANKH were set to Craniometaphyseal dysplasia, OMIM:123000; craniosynostosis, MONDO:0015469
Review for gene: ANKH was set to AMBER
Added comment: PMID:36118902 reported a single patient with variant in ANKH (c.1129_1132delinsC; p.Phe377del) from a Chinese cohort with syndromic bicoronal and sagittal synostosis. This variant is reported as pathogenic for craniometaphyseal dysplasia in ClinVar and is absent from gnomAD v.2.1.1.

DECIPHER database (https://www.deciphergenomics.org) reported craniosynostosis as one of the clinical presentations in a single patient with heterozygous sequence variant (c.559C​>T; p.Arg187Trp) in ANKH gene. This variant was reported as likely pathogenic.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.103 ACVRL1 Achchuthan Shanmugasundram changed review comment from: PMID:35997807 reported a cohort of patients with lambdoid synostosis, where a de novo variant (p.Val228Ile) in was identified in ACVRL1. Hence, this gene should be added with a red rating.
Sources: Literature; to: PMID:35997807 reported a cohort of patients with lambdoid synostosis, where a de novo variant (p.Val228Ile) was identified in ACVRL1. Hence, this gene should be added with a red rating.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.103 ACVR2A Achchuthan Shanmugasundram gene: ACVR2A was added
gene: ACVR2A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ACVR2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ACVR2A were set to 35997807; 36980886
Phenotypes for gene: ACVR2A were set to craniosynostosis, MONDO:0015469
Review for gene: ACVR2A was set to RED
Added comment: PMID:35997807 reported a cohort of patients with lambdoid synostosis, where a de novo variant (p.Thr63Ala) was identified in ACVR2A. Hence, this gene should be added with a red rating.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.102 ACVRL1 Achchuthan Shanmugasundram Phenotypes for gene: ACVRL1 were changed from to craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.101 ACVRL1 Achchuthan Shanmugasundram edited their review of gene: ACVRL1: Changed phenotypes to: craniosynostosis, MONDO:0015469
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.101 ACVRL1 Achchuthan Shanmugasundram gene: ACVRL1 was added
gene: ACVRL1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature
Mode of inheritance for gene: ACVRL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ACVRL1 were set to 35997807; 36980886
Review for gene: ACVRL1 was set to RED
Added comment: PMID:35997807 reported a cohort of patients with lambdoid synostosis, where a de novo variant (p.Val228Ile) in was identified in ACVRL1. Hence, this gene should be added with a red rating.
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.100 ABCC9 Achchuthan Shanmugasundram changed review comment from: PMID:24352916 reported a Japanese family with Cantu syndrome, of which the boy had bicoronal synostosis, which was absent in the father. This gene should only be rated red as there is only one case reported so far.; to: PMID:24352916 reported a Japanese family with Cantu syndrome, of which the boy had bicoronal synostosis, which was absent in the father. Craniosynostosis has not previously been reported as part of Cantu syndrome. This gene should only be rated red as there is only one case reported so far.
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.100 ABCC9 Achchuthan Shanmugasundram Publications for gene: ABCC9 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.99 ABCC9 Achchuthan Shanmugasundram Mode of inheritance for gene: ABCC9 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.98 ABCC9 Achchuthan Shanmugasundram reviewed gene: ABCC9: Rating: RED; Mode of pathogenicity: None; Publications: 24352916, 36980886; Phenotypes: Hypertrichotic osteochondrodysplasia (Cantu syndrome), OMIM: 239850; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paroxysmal central nervous system disorders v3.1 ALPK1 Dmitrijs Rots gene: ALPK1 was added
gene: ALPK1 was added to Paroxysmal central nervous system disorders. Sources: Literature
Mode of inheritance for gene: ALPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALPK1 were set to PMID: 30967659
Phenotypes for gene: ALPK1 were set to ROSAH syndrome
Mode of pathogenicity for gene: ALPK1 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: ALPK1 was set to GREEN
Added comment: ALPK1 is associated with ROSAH syndrome, which commonly include episodic migraine or other headaches.
Sources: Literature
Severe microcephaly v4.28 BUB1 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.205
Severe microcephaly v4.28 BUB1 Arina Puzriakova gene: BUB1 was added
gene: BUB1 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
Q4_22_promote_green tags were added to gene: BUB1.
Mode of inheritance for gene: BUB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1 were set to 35044816
Phenotypes for gene: BUB1 were set to Microcephaly 30, primary, autosomal recessive, OMIM:620183
Penetrance for gene: BUB1 were set to Complete
Intellectual disability v5.205 BUB1 Arina Puzriakova Phenotypes for gene: BUB1 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability; Abnormal heart morphology; Growth delay to Microcephaly 30, primary, autosomal recessive, OMIM:620183
Intellectual disability v5.204 BUB1 Arina Puzriakova commented on gene: BUB1
Intellectual disability v5.204 BUB1 Arina Puzriakova Tag Q4_22_MOI was removed from gene: BUB1.
Dilated and arrhythmogenic cardiomyopathy v2.11 TAB2 Arina Puzriakova Entity copied from Paediatric or syndromic cardiomyopathy v3.15
Dilated and arrhythmogenic cardiomyopathy v2.11 TAB2 Arina Puzriakova gene: TAB2 was added
gene: TAB2 was added to Dilated and arrhythmogenic cardiomyopathy. Sources: Expert Review Amber,NHS GMS,London South GLH
Q3_23_promote_green tags were added to gene: TAB2.
Mode of inheritance for gene: TAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TAB2 were set to 28464518; 29700987; 32183715; 34456334; 34990405; 34741306; 36000780; 37153890
Phenotypes for gene: TAB2 were set to Congenital heart defects, nonsyndromic, 2, OMIM:614980
Paediatric disorders - additional genes v3.3 TAB2 Arina Puzriakova Entity copied from Paediatric or syndromic cardiomyopathy v3.15
Paediatric disorders - additional genes v3.3 TAB2 Arina Puzriakova gene: TAB2 was added
gene: TAB2 was added to Paediatric disorders - additional genes. Sources: Expert Review Amber,NHS GMS,London South GLH
Q3_23_promote_green tags were added to gene: TAB2.
Mode of inheritance for gene: TAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TAB2 were set to 28464518; 29700987; 32183715; 34456334; 34990405; 34741306; 36000780; 37153890
Phenotypes for gene: TAB2 were set to Congenital heart defects, nonsyndromic, 2, OMIM:614980
Paediatric or syndromic cardiomyopathy v3.15 TAB2 Arina Puzriakova Classified gene: TAB2 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v3.15 TAB2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Paediatric or syndromic cardiomyopathy v3.15 TAB2 Arina Puzriakova Gene: tab2 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v3.14 TAB2 Arina Puzriakova Mode of inheritance for gene: TAB2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric or syndromic cardiomyopathy v3.13 TAB2 Arina Puzriakova Publications for gene: TAB2 were set to
Paediatric or syndromic cardiomyopathy v3.12 TAB2 Arina Puzriakova Tag Q3_23_promote_green tag was added to gene: TAB2.
Paediatric or syndromic cardiomyopathy v3.12 TAB2 Arina Puzriakova edited their review of gene: TAB2: Changed publications to: 28464518, 29700987, 32183715, 34456334, 34990405, 34741306, 36000780, 37153890; Changed phenotypes to: Congenital heart defects, nonsyndromic, 2, OMIM:614980
Paediatric or syndromic cardiomyopathy v3.12 TAB2 Arina Puzriakova reviewed gene: TAB2: Rating: GREEN; Mode of pathogenicity: None; Publications: Congenital heart defects, nonsyndromic, 2, OMIM:614980; Phenotypes: 28464518, 29700987, 32183715, 34456334, 34990405, 34741306, 36000780, 37153890; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Infantile nystagmus v1.6 DAGLA Irina Ziravecka gene: DAGLA was added
gene: DAGLA was added to Infantile nystagmus. Sources: Literature
Mode of inheritance for gene: DAGLA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DAGLA were set to PMID: 35737950
Phenotypes for gene: DAGLA were set to developmental delay; ataxia; complex oculomotor abnormality (nystagmus)
Mode of pathogenicity for gene: DAGLA was set to Other
Review for gene: DAGLA was set to GREEN
Added comment: PMID: 35737950 - nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype.
Sources: Literature
Hereditary ataxia v1.326 DAGLA Irina Ziravecka gene: DAGLA was added
gene: DAGLA was added to Hereditary ataxia. Sources: Literature
Mode of inheritance for gene: DAGLA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DAGLA were set to PMID: 35737950
Phenotypes for gene: DAGLA were set to developmental delay; ataxia; complex oculomotor abnormality
Mode of pathogenicity for gene: DAGLA was set to Other
Review for gene: DAGLA was set to GREEN
Added comment: PMID: 35737950 - nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype.
Sources: Literature
Intellectual disability v5.204 DAGLA Irina Ziravecka gene: DAGLA was added
gene: DAGLA was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: DAGLA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DAGLA were set to PMID: 35737950
Phenotypes for gene: DAGLA were set to developmental delay; ataxia; complex oculomotor abnormality
Mode of pathogenicity for gene: DAGLA was set to Other
Review for gene: DAGLA was set to GREEN
Added comment: PMID: 35737950 - nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.22 MECOM Boaz Palterer gene: MECOM was added
gene: MECOM was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: MECOM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MECOM were set to 37407873
Phenotypes for gene: MECOM were set to Radioulnar synostosis with amegakaryocytic thrombocytopenia 2, OMIM:616738; Hypocellular bone marrow; congenital thrombocytopenia; B-cell lymphopenia; hypogammaglobulinemia; radioulnar synostosis; digit abnormalities; clubfoot; cardiac defects; facial dysmorphism
Penetrance for gene: MECOM were set to unknown
Review for gene: MECOM was set to GREEN
Added comment: Bone marrow failure syndrome included in the 2022 IUIS IEI classification. A subset of patients presents B cell deficiency and hypogammaglobulinemia. The phenotype is relevant for the panel.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v3.17 TMEM151A Lucy Jackson edited their review of gene: TMEM151A: Changed publications to: 34518509, 35707035, 36724570, 34820915
Childhood onset dystonia, chorea or related movement disorder v3.17 TMEM151A Lucy Jackson gene: TMEM151A was added
gene: TMEM151A was added to Childhood onset dystonia, chorea or related movement disorder. Sources: NHS GMS
Mode of inheritance for gene: TMEM151A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM151A were set to (PMID: 34518509; 35707035; 36724570; 34820915)
Phenotypes for gene: TMEM151A were set to Episodic kinesigenic dyskinesia 3
Review for gene: TMEM151A was set to GREEN
Added comment: LOF variants have been shown to cause autosomal dominant Episodic kinesigenic dyskinesia 3
Sources: NHS GMS
Adult onset neurodegenerative disorder v4.28 PPP2R2B_CAG Sarah Leigh Deleted their review
Adult onset neurodegenerative disorder v4.28 PPP2R2B_CAG Sarah Leigh Tag Q3_23_promote_green was removed from STR: PPP2R2B_CAG.
Adult onset neurodegenerative disorder v4.28 NOP56_GGCCTG Sarah Leigh Deleted their review
Adult onset neurodegenerative disorder v4.28 NOP56_GGCCTG Sarah Leigh Tag Q3_23_promote_green was removed from STR: NOP56_GGCCTG.
Adult onset neurodegenerative disorder v4.28 FXN_GAA Sarah Leigh Deleted their review
Adult onset neurodegenerative disorder v4.28 FXN_GAA Sarah Leigh Tag Q3_23_promote_green was removed from STR: FXN_GAA.
Adult onset neurodegenerative disorder v4.28 CSTB_CCCCGCCCCGCG Sarah Leigh Deleted their review
Adult onset neurodegenerative disorder v4.28 CSTB_CCCCGCCCCGCG Sarah Leigh Tag Q3_23_promote_green was removed from STR: CSTB_CCCCGCCCCGCG.
Adult onset neurodegenerative disorder v4.28 CACNA1A_CAG Sarah Leigh Deleted their review
Adult onset neurodegenerative disorder v4.28 CACNA1A_CAG Sarah Leigh Tag Q3_23_promote_green was removed from STR: CACNA1A_CAG.
Adult onset neurodegenerative disorder v4.28 ATXN7_CAG Sarah Leigh Deleted their review
Adult onset neurodegenerative disorder v4.28 ATXN7_CAG Sarah Leigh Tag Q3_23_promote_green was removed from STR: ATXN7_CAG.
Adult onset neurodegenerative disorder v4.28 ATXN3_CAG Sarah Leigh Deleted their review
Adult onset neurodegenerative disorder v4.28 ATXN3_CAG Sarah Leigh Tag Q3_23_promote_green was removed from STR: ATXN3_CAG.
Adult onset neurodegenerative disorder v4.28 ATXN2_CAG Sarah Leigh Deleted their review
Adult onset neurodegenerative disorder v4.28 ATXN2_CAG Sarah Leigh Tag Q3_23_promote_green was removed from STR: ATXN2_CAG.
Adult onset neurodegenerative disorder v4.28 ATXN10_ATTCT Sarah Leigh Deleted their review
Adult onset neurodegenerative disorder v4.28 ATXN1_CAG Sarah Leigh Deleted their review
Adult onset neurodegenerative disorder v4.28 ATXN1_CAG Sarah Leigh Deleted their comment
Adult onset neurodegenerative disorder v4.28 ATXN1_CAG Sarah Leigh Tag Q3_23_promote_green was removed from STR: ATXN1_CAG.
Adult onset neurodegenerative disorder v4.28 ATXN10_ATTCT Sarah Leigh Deleted their comment
Adult onset neurodegenerative disorder v4.28 ATXN10_ATTCT Sarah Leigh Tag Q3_23_promote_green was removed from STR: ATXN10_ATTCT.
Mitochondrial disorders v4.56 SLC22A5 Sarah Leigh changed review comment from: Numerous SLC22A5 variants are associated with a relevant phenotype in OMIM (OMIM:212140) and SLC22A5 has a definitive association in Gen2Phen for Systemic Carnitine Deficiency. A supportive mouse model has also been reported (PMID: 17884651).; to: Numerous SLC22A5 variants have been associated with OMIM:212140, and SLC22A5 has a definitive association in Gen2Phen for Systemic Carnitine Deficiency. A supportive mouse model has also been reported (PMID: 17884651).
Mitochondrial disorders v4.56 SLC22A5 Sarah Leigh edited their review of gene: SLC22A5: Added comment: Numerous SLC22A5 variants are associated with a relevant phenotype in OMIM (OMIM:212140) and SLC22A5 has a definitive association in Gen2Phen for Systemic Carnitine Deficiency. A supportive mouse model has also been reported (PMID: 17884651).; Changed rating: GREEN
Mitochondrial disorders v4.56 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 9916797; 17884651; 25778941
Mitochondrial disorders v4.55 SLC22A5 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: SLC22A5.
Mitochondrial disorders v4.55 SLC22A5 Sarah Leigh Classified gene: SLC22A5 as Amber List (moderate evidence)
Mitochondrial disorders v4.55 SLC22A5 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v4.55 SLC22A5 Sarah Leigh Gene: slc22a5 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.54 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to 9916797; 25778941; 17884651; 25778941
Mitochondrial disorders v4.53 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from Carnitine deficiency, systemic primary, 212140 to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Mitochondrial disorders v4.52 SLC22A5 Sarah Leigh Publications for gene: SLC22A5 were set to
RASopathies v1.78 MAP4K4 Irina Ziravecka gene: MAP4K4 was added
gene: MAP4K4 was added to RASopathies. Sources: Literature
Mode of inheritance for gene: MAP4K4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP4K4 were set to PMID: 37126546
Phenotypes for gene: MAP4K4 were set to neurodevelopmental differences; multiple congenital anomalies
Mode of pathogenicity for gene: MAP4K4 was set to Other
Review for gene: MAP4K4 was set to GREEN
Added comment: PMID: 37126546 - "a cohort of 26 affected individuals from 21 unrelated families with neurodevelopmental differences, cardiac issues, and CFAs who share a phenotype overlap with RASopathies and harbor a series of rare variants in MAP4K4.
Functional studies in zebrafish showed that MAP4K4 variants caused hypomorphic, LOF, or DN effects."
Sources: Literature
DDG2P v3.6 MAP4K4 Irina Ziravecka gene: MAP4K4 was added
gene: MAP4K4 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: MAP4K4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP4K4 were set to PMID: 37126546
Phenotypes for gene: MAP4K4 were set to neurodevelopmental differences; multiple congenital anomalies
Mode of pathogenicity for gene: MAP4K4 was set to Other
Review for gene: MAP4K4 was set to GREEN
Added comment: PMID: 37126546 - "a cohort of 26 affected individuals from 21 unrelated families with neurodevelopmental differences, cardiac issues, and CFAs who share a phenotype overlap with RASopathies and harbor a series of rare variants in MAP4K4.
Functional studies in zebrafish showed that MAP4K4 variants caused hypomorphic, LOF, or DN effects."
Sources: Literature
DDG2P v3.6 AMOTL1 Irina Ziravecka edited their review of gene: AMOTL1: Added comment: PMID: 36751037 - this cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157–161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.
5 out of 16 patients in this cohort have developmental delay.; Changed phenotypes to: orofacial clefting, cardiac anomalies, tall stature, distinct dysmorphisms (abnormal head shape, craniosynostosis, hypertelorism, and large ears), myopia, hearing loss, micrognathia, immune dysfunction, scoliosis, chronic constipation, liver dysfunction, global developmental delay
DDG2P v3.6 AMOTL1 Irina Ziravecka Deleted their comment
DDG2P v3.6 AMOTL1 Irina Ziravecka changed review comment from: PMID: 36751037 - this cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157–161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.
Sources: Other; to: PMID: 36751037 - this cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157–161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.
5 out of 16 patients in this cohort have developmental delay.
DDG2P v3.6 AMOTL1 Irina Ziravecka gene: AMOTL1 was added
gene: AMOTL1 was added to DDG2P. Sources: Other
Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMOTL1 were set to PMID: 36751037
Phenotypes for gene: AMOTL1 were set to orofacial clefting; cardiac anomalies; tall stature
Mode of pathogenicity for gene: AMOTL1 was set to Other
Review for gene: AMOTL1 was set to GREEN
Added comment: PMID: 36751037 - this cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157–161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.
Sources: Other
Clefting v4.78 AMOTL1 Irina Ziravecka reviewed gene: AMOTL1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 36751037; Phenotypes: orofacial clefting, cardiac anomalies, tall stature; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v4.10 SETD5 Tracy Lester gene: SETD5 was added
gene: SETD5 was added to Skeletal dysplasia. Sources: NHS GMS
Mode of inheritance for gene: SETD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SETD5 were set to 28881385
Phenotypes for gene: SETD5 were set to Skeletal dysplasia; intellectual disability; developmental delay; facial dysmorphism
Penetrance for gene: SETD5 were set to Incomplete
Review for gene: SETD5 was set to GREEN
Added comment: This gene is associated with an autosomal dominant neurodevelopmental disorder characterised by developmental delay, intellectual disability, and variable dysmorphic and skeletal abnormalities. Expressivity is variable and non-penetrance has been reported. As the skeletal features might appear before the ID/DD I think this gene should be added to the SD panel. We recently found a pathogenic fs in this gene in a child with short stature, short long bones and facial dysmorphism but without mention of DD/ID; however case was only 10m old at referral.
Sources: NHS GMS
Hereditary ataxia with onset in adulthood v4.15 PRPS1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: All female cases from the three families were reported with X-linked dominant variants in PRPS1 gene. Hence, the MOI should be changed to "X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)".
Hereditary ataxia with onset in adulthood v4.15 PRPS1 Achchuthan Shanmugasundram Mode of inheritance for gene: PRPS1 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)
Hereditary ataxia with onset in adulthood v4.14 PRPS1 Achchuthan Shanmugasundram Phenotypes for gene: PRPS1 were changed from Ataxia; deafness; eye disease to cerebellar ataxia, MONDO:0000437
Hereditary ataxia with onset in adulthood v4.13 PRPS1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Three families reported with adult-onset ataxia. Although ataxia has been reported in the proband and her mother with X-linked dominant variant in a family in PMID:28967191, it was not reported in the older sister from the family with the same variant. Due to the reduced penetrance in this family, this gene should only be rated amber.; to: Comment on list classification: As reviewed by Zornitza Stark, three families were reported with adult-onset ataxia. Although ataxia has been reported in the proband and her mother with X-linked dominant variant in a family in PMID:28967191, it was not reported in the older sister from the family with the same variant. Due to the reduced penetrance in this family, this gene should only be rated amber.
Hereditary ataxia with onset in adulthood v4.13 PRPS1 Achchuthan Shanmugasundram Classified gene: PRPS1 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v4.13 PRPS1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Three families reported with adult-onset ataxia. Although ataxia has been reported in the proband and her mother with X-linked dominant variant in a family in PMID:28967191, it was not reported in the older sister from the family with the same variant. Due to the reduced penetrance in this family, this gene should only be rated amber.
Hereditary ataxia with onset in adulthood v4.13 PRPS1 Achchuthan Shanmugasundram Gene: prps1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v4.12 PRPS1 Achchuthan Shanmugasundram reviewed gene: PRPS1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25491489, 28967191, 33898739; Phenotypes: cerebellar ataxia, MONDO:0000437; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v5.204 PTPA Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.204 PTPA Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.204 PTPA Achchuthan Shanmugasundram Classified gene: PTPA as Amber List (moderate evidence)
Intellectual disability v5.204 PTPA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are two unrelated cases with intellectual disability and hence this gene should be rated amber.
Intellectual disability v5.204 PTPA Achchuthan Shanmugasundram Gene: ptpa has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Classified gene: PTPA as Amber List (moderate evidence)
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are two unrelated cases with intellectual disability and hence this gene should be rated amber.
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Gene: ptpa has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Classified gene: PTPA as Amber List (moderate evidence)
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are two unrelated cases with intellectual disability and hence this gene should be rated amber.
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Gene: ptpa has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Classified gene: PTPA as Amber List (moderate evidence)
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are two unrelated cases with intellectual disability and hence this gene should be rated amber.
Intellectual disability v5.203 PTPA Achchuthan Shanmugasundram Gene: ptpa has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.202 PTPA Achchuthan Shanmugasundram Phenotypes for gene: PTPA were changed from Intellectual disability, MONDO:0001071 to Intellectual disability, MONDO:0001071
Intellectual disability v5.202 PTPA Achchuthan Shanmugasundram Phenotypes for gene: PTPA were changed from Intellectual disability, MONDO:0001071 to Intellectual disability, MONDO:0001071
Intellectual disability v5.201 PTPA Achchuthan Shanmugasundram Phenotypes for gene: PTPA were changed from Intellectual disability, MONDO:0001071 to Intellectual disability, MONDO:0001071
Intellectual disability v5.201 PTPA Achchuthan Shanmugasundram Phenotypes for gene: PTPA were changed from Intellectual disability, MONDO:0001071 to Intellectual disability, MONDO:0001071
Intellectual disability v5.201 PTPA Achchuthan Shanmugasundram Phenotypes for gene: PTPA were changed from Intellectual disability; Parkinsonism to Intellectual disability, MONDO:0001071
Intellectual disability v5.200 PTPA Achchuthan Shanmugasundram reviewed gene: PTPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36073231; Phenotypes: Intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Classified gene: FOXR1 as Amber List (moderate evidence)
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Gene: foxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.; to: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay supported by functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Classified gene: FOXR1 as Amber List (moderate evidence)
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Gene: foxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Classified gene: FOXR1 as Amber List (moderate evidence)
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Gene: foxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Classified gene: FOXR1 as Amber List (moderate evidence)
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.200 FOXR1 Achchuthan Shanmugasundram Gene: foxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Classified gene: FOXR1 as Amber List (moderate evidence)
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Gene: foxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Classified gene: FOXR1 as Amber List (moderate evidence)
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Gene: foxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Classified gene: FOXR1 as Amber List (moderate evidence)
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Gene: foxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Classified gene: FOXR1 as Amber List (moderate evidence)
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with global developmental delay and supporting functional evidence including mouse model. Hence, this gene should be rated amber.
Intellectual disability v5.199 FOXR1 Achchuthan Shanmugasundram Gene: foxr1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.198 FOXR1 Achchuthan Shanmugasundram Phenotypes for gene: FOXR1 were changed from Global developmental delay, HP:0001263; microcephaly, MONDO:0001149; Brain atrophy, HP:0012444 to Global developmental delay, HP:0001263; microcephaly, MONDO:0001149; Brain atrophy, HP:0012444
Intellectual disability v5.198 FOXR1 Achchuthan Shanmugasundram Phenotypes for gene: FOXR1 were changed from Global developmental delay, HP:0001263; microcephaly, MONDO:0001149; Brain atrophy, HP:0012444 to Global developmental delay, HP:0001263; microcephaly, MONDO:0001149; Brain atrophy, HP:0012444
Intellectual disability v5.198 FOXR1 Achchuthan Shanmugasundram Phenotypes for gene: FOXR1 were changed from Global developmental delay, HP:0001263; microcephaly, MONDO:0001149; Brain atrophy, HP:0012444 to Global developmental delay, HP:0001263; microcephaly, MONDO:0001149; Brain atrophy, HP:0012444
Intellectual disability v5.198 FOXR1 Achchuthan Shanmugasundram Phenotypes for gene: FOXR1 were changed from Global developmental delay, HP:0001263; microcephaly, MONDO:0001149; Brain atrophy, HP:0012444 to Global developmental delay, HP:0001263; microcephaly, MONDO:0001149; Brain atrophy, HP:0012444
Intellectual disability v5.197 FOXR1 Achchuthan Shanmugasundram Phenotypes for gene: FOXR1 were changed from Global developmental delay, HP:0001263; microcephaly, MONDO:0001149; Brain atrophy, HP:0012444 to Global developmental delay, HP:0001263; microcephaly, MONDO:0001149; Brain atrophy, HP:0012444
Intellectual disability v5.197 FOXR1 Achchuthan Shanmugasundram Phenotypes for gene: FOXR1 were changed from Postnatal microcephaly, progressive brain atrophy and global developmental delay to Global developmental delay, HP:0001263; microcephaly, MONDO:0001149; Brain atrophy, HP:0012444
Intellectual disability v5.196 FOXR1 Achchuthan Shanmugasundram edited their review of gene: FOXR1: Changed phenotypes to: Global developmental delay, HP:0001263, microcephaly, MONDO:0001149, Brain atrophy, HP:0012444
Intellectual disability v5.196 FOXR1 Achchuthan Shanmugasundram reviewed gene: FOXR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34723967; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Renal tubulopathies v4.1 RMND1 John Sayer gene: RMND1 was added
gene: RMND1 was added to Renal tubulopathies. Sources: Expert list
Mode of inheritance for gene: RMND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RMND1 were set to 32911714; 31889854; 31568715
Phenotypes for gene: RMND1 were set to tubulopathy; renal tubular acidosis; interstitial nephritis; end-stage renal disease; tubular atrophy
Penetrance for gene: RMND1 were set to Complete
Mode of pathogenicity for gene: RMND1 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: RMND1 was set to GREEN
Added comment: Sources: Expert list
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v0.1 HBB Achchuthan Shanmugasundram changed review comment from: HBB has been added to the panel for R288 GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB with a green rating as agreed with the NHS Genomic Medicine Service.; to: HBB has been added to the panel for R361 Haemoglobinopathy trait or carrier testing with a green rating as agreed with the NHS Genomic Medicine Service.
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v0.1 HBA1 Achchuthan Shanmugasundram changed review comment from: HBA1 has been added to the panel for R288 GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB with a green rating as agreed with the NHS Genomic Medicine Service.; to: HBA1 has been added to the panel for R361 Haemoglobinopathy trait or carrier testing with a green rating as agreed with the NHS Genomic Medicine Service.
Intellectual disability v5.196 KDM6B Sarah Leigh Phenotypes for gene: KDM6B were changed from Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505 to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, OMIM:618505; neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, MONDO:0032790
Early onset or syndromic epilepsy v4.67 KDM6B Sarah Leigh edited their review of gene: KDM6B: Added comment: KDM6B variants have been associated with relevant phenotype in OMIM and as strong Gen2Phen gene for KDM6B-related developmental disorder (monoallelic). PMID: 37196654 reports that in their cohort, 9/69 (13%) of individuals had seizures.; Changed rating: GREEN
Early onset or syndromic epilepsy v4.67 KDM6B Sarah Leigh Classified gene: KDM6B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.67 KDM6B Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v4.67 KDM6B Sarah Leigh Gene: kdm6b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.66 KDM6B Sarah Leigh Tag Q3_23_promote_green tag was added to gene: KDM6B.
Early onset or syndromic epilepsy v4.66 KDM6B Sarah Leigh Phenotypes for gene: KDM6B were changed from Global developmental delay; Intellectual disability; Hypotonia; Joint hypermobility; seizures; Overgrowth to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, OMIM:618505; neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, MONDO:0032790
Early onset or syndromic epilepsy v4.65 KDM6B Sarah Leigh Publications for gene: KDM6B were set to PMID: 37196654
Intellectual disability v5.195 KDM6B Sarah Leigh Publications for gene: KDM6B were set to 21937992; 31124279
Early onset or syndromic epilepsy v4.64 DALRD3 Arina Puzriakova Classified gene: DALRD3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.64 DALRD3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as this is a good candidate gene but only a single family has been reported to date with variants. Additional evidence needed prior to adding the gene as diagnostic-grade.
Early onset or syndromic epilepsy v4.64 DALRD3 Arina Puzriakova Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.63 DALRD3 Arina Puzriakova Classified gene: DALRD3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.63 DALRD3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as this is a good candidate gene but only a single family has been reported to date with variants. Additional evidence needed prior to adding the gene as diagnostic-grade.
Early onset or syndromic epilepsy v4.63 DALRD3 Arina Puzriakova Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v5.194 DALRD3 Arina Puzriakova Classified gene: DALRD3 as Amber List (moderate evidence)
Intellectual disability v5.194 DALRD3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as this is a good candidate gene but only a single family has been reported to date with variants. Additional evidence needed prior to adding the gene as diagnostic-grade.
Intellectual disability v5.194 DALRD3 Arina Puzriakova Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Familial breast cancer v1.20 ATRIP Arina Puzriakova Mode of inheritance for gene: ATRIP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial breast cancer v1.19 ATRIP Arina Puzriakova Classified gene: ATRIP as Amber List (moderate evidence)
Familial breast cancer v1.19 ATRIP Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane. More evidence is required prior to adding this gene to the panel. The metanalysis paper identified by reviewer is still at the preprint stage. The findings are detailed below but this needs to be revisited once the article has been published. This is a good candidate gene for breast cancer susceptibility but for now can only classify as Amber (with watchlist tag), awaiting peer-review and additional publication of supporting evidence.
Familial breast cancer v1.19 ATRIP Arina Puzriakova Gene: atrip has been classified as Amber List (Moderate Evidence).
Familial breast cancer v1.18 ATRIP Arina Puzriakova commented on gene: ATRIP
Breast cancer pertinent cancer susceptibility v2.2 ATRIP Arina Puzriakova changed review comment from: Enrichment for ATRIP variants was found in meta-analysis of breast cancer cohorts and UK Biobank. ATRIP carriers had a higher proportion of high-grade, low-stage ductal breast cancer but none of the associations with tumor characteristics were statistically significant.

Another study (PMID: 36977412) also identified three Polish women with familial breast cancer and variants in this gene including a c.69_75dup (p.Thr26Alafs∗23) frameshift insertion (not discussed further in paper) and a founder c.1152_1155del (p.Gly385Ter) frameshift deletion in two women. The founder variant was also found in validation cohorts with 42/16,085 unselected Polish breast cancer-affected individuals and 11/9,285 control subjects (OR = 2.14, 95% CI = 1.13-4.28, p = 0.02) harbouring the variant. UK Biobank data showed ATRIP loss-of-function variants among 13/15,643 breast cancer-affected individuals versus 40/157,943 control subjects (OR = 3.28, 95% CI = 1.76-6.14, p < 0.001).

Immunohistochemistry and functional studies showed the ATRIP c.1152_1155del variant allele is weakly expressed compared to the wild-type allele, and truncated ATRIP fails to perform its normal function to prevent replicative stress.
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ATRIP is currently not associated with any phenotype in OMIM or G2P. It codes for a DNA damage response protein which forms a complex with ATR. ATR-ATRIP is involved in the process that activates checkpoint signalling when single-stranded DNA is detected following the processing of DNA double-stranded breaks or stalled replication forks.; to: Enrichment for ATRIP variants was found in meta-analysis of breast cancer cohorts and UK Biobank. ATRIP carriers had a higher proportion of high-grade, low-stage ductal breast cancer but none of the associations with tumor characteristics were statistically significant (https://doi.org/10.1101/2022.06.17.22276537).

Another study (PMID: 36977412) also identified three Polish women with familial breast cancer and variants in this gene including a c.69_75dup (p.Thr26Alafs∗23) frameshift insertion (not discussed further in paper) and a founder c.1152_1155del (p.Gly385Ter) frameshift deletion in two women. The founder variant was also found in validation cohorts with 42/16,085 unselected Polish breast cancer-affected individuals and 11/9,285 control subjects (OR = 2.14, 95% CI = 1.13-4.28, p = 0.02) harbouring the variant. UK Biobank data showed ATRIP loss-of-function variants among 13/15,643 breast cancer-affected individuals versus 40/157,943 control subjects (OR = 3.28, 95% CI = 1.76-6.14, p < 0.001).

Immunohistochemistry and functional studies showed the ATRIP c.1152_1155del variant allele is weakly expressed compared to the wild-type allele, and truncated ATRIP fails to perform its normal function to prevent replicative stress.
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ATRIP is currently not associated with any phenotype in OMIM or G2P. It codes for a DNA damage response protein which forms a complex with ATR. ATR-ATRIP is involved in the process that activates checkpoint signalling when single-stranded DNA is detected following the processing of DNA double-stranded breaks or stalled replication forks.
Breast cancer pertinent cancer susceptibility v2.2 ATRIP Arina Puzriakova Classified gene: ATRIP as Amber List (moderate evidence)
Breast cancer pertinent cancer susceptibility v2.2 ATRIP Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane. More evidence is required prior to adding this gene to the panel. The metanalysis paper identified by reviewer is still at the preprint stage. The findings are detailed below but this needs to be revisited once the article has been published. This is a good candidate gene for breast cancer susceptibility but for now can only classify as Amber (with watchlist tag), awaiting peer-review and additional publication of supporting evidence.
Breast cancer pertinent cancer susceptibility v2.2 ATRIP Arina Puzriakova Gene: atrip has been classified as Amber List (Moderate Evidence).
Breast cancer pertinent cancer susceptibility v2.1 ATRIP Arina Puzriakova Tag watchlist tag was added to gene: ATRIP.
Breast cancer pertinent cancer susceptibility v2.1 ATRIP Arina Puzriakova commented on gene: ATRIP
Intellectual disability v5.193 SMCHD1 Arina Puzriakova Mode of inheritance for gene: SMCHD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Facioscapulohumeral muscular dystrophy - extended testing v0.1 SMCHD1 Arina Puzriakova Tag digenic tag was added to gene: SMCHD1.
Inherited polyposis and early onset colorectal cancer - germline testing v2.6 GREM1 Arina Puzriakova Mode of pathogenicity for gene: GREM1 was changed from to Other
Adult solid tumours for rare disease v1.36 PDGFRA Sumir Pandit reviewed gene: PDGFRA: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 29486293; Phenotypes: ; Mode of inheritance: None
Inherited polyposis and early onset colorectal cancer - germline testing v2.5 GREM1 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes:
Hereditary Mixed Polyposis Syndrome;Oligosyndactyly of the hands, Cenani-Linz-like (Dimitrov (2010) J Med Genet 47,569);Polyposis Syndrome, Hereditary Mixed, 1;Mixed polyposis syndrome (Jaeger (2012) Nat Genet 44,699);{Colorectal cancer, increased risk, association with}(Peters (2012) Hum Genet 131,217)
Inherited polyposis and early onset colorectal cancer - germline testing v2.5 GREM1 Arina Puzriakova Phenotypes for gene: GREM1 were changed from Hereditary Mixed Polyposis Syndrome; Oligosyndactyly of the hands, Cenani-Linz-like (Dimitrov (2010) J Med Genet 47,569); Polyposis Syndrome, Hereditary Mixed, 1; Mixed polyposis syndrome (Jaeger (2012) Nat Genet 44,699); {Colorectal cancer, increased risk, association with}(Peters (2012) Hum Genet 131,217) to Hereditary mixed polyposis syndrome, MONDO:0011023
Paediatric or syndromic cardiomyopathy v3.12 ELAC2 Matthew Edwards gene: ELAC2 was added
gene: ELAC2 was added to Paediatric or syndromic cardiomyopathy. Sources: Expert Review
Mode of inheritance for gene: ELAC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ELAC2 were set to PMID: 23849775
Penetrance for gene: ELAC2 were set to unknown
Review for gene: ELAC2 was set to GREEN
Added comment: Oxidative phosphorylation deficiency-17 manifests as severe infantile-onset hypertrophic cardiomyopathy (green gene on several metabolic panels, but presenting feature is HCM in first year of life)

Also recent diagnostic case through our GLH
Sources: Expert Review
Retinal disorders v4.12 MCOLN1 Siying Lin gene: MCOLN1 was added
gene: MCOLN1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: MCOLN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCOLN1 were set to 17239335; 1488220; 18326692
Mode of pathogenicity for gene: MCOLN1 was set to Other
Review for gene: MCOLN1 was set to GREEN
Added comment: Retinal degeneration is a known feature of MCOLN1-associated mucolipidosis IV, and there are reports of patients presenting with a limited ocular phenotype including retinal dystrophy
Sources: Literature
Hereditary ataxia v1.326 DMXL2 Arina Puzriakova Mode of inheritance for gene: DMXL2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.17 DMXL2 Arina Puzriakova Mode of inheritance for gene: DMXL2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.16 DMXL2 Arina Puzriakova Classified gene: DMXL2 as Red List (low evidence)
Ataxia and cerebellar anomalies - narrow panel v4.16 DMXL2 Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red. Ataxia (onset in adolescence) has only been reported in one consanguineous family to date (PMID: 25248098) and this finding has not since been replicated. Therefore demoting the gene rating, inline with review by Dmitrijs Rots.
Ataxia and cerebellar anomalies - narrow panel v4.16 DMXL2 Arina Puzriakova Gene: dmxl2 has been classified as Red List (Low Evidence).
Hereditary ataxia v1.325 DMXL2 Arina Puzriakova Publications for gene: DMXL2 were set to 27657680; 22875945; 25248098
Ataxia and cerebellar anomalies - narrow panel v4.15 DMXL2 Arina Puzriakova Publications for gene: DMXL2 were set to 25248098; 22875945; 27657680
Hereditary ataxia v1.324 DMXL2 Arina Puzriakova Phenotypes for gene: DMXL2 were changed from ?Polyendocrine-polyneuropathy syndrome , OMIM:616113 to ?Polyendocrine-polyneuropathy syndrome, OMIM:616113
Ataxia and cerebellar anomalies - narrow panel v4.14 DMXL2 Arina Puzriakova Phenotypes for gene: DMXL2 were changed from Sensorineural Hearing Loss; ORPHA90636; OMIM:612186 to ?Polyendocrine-polyneuropathy syndrome, OMIM:616113
Hereditary ataxia v1.323 DMXL2 Arina Puzriakova Phenotypes for gene: DMXL2 were changed from Sensorineural Hearing Loss; ORPHA90636; OMIM:612186 to ?Polyendocrine-polyneuropathy syndrome , OMIM:616113
Hereditary ataxia v1.322 DMXL2 Arina Puzriakova Classified gene: DMXL2 as Red List (low evidence)
Hereditary ataxia v1.322 DMXL2 Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red. Ataxia (onset in adolescence) has only been reported in one consanguineous family to date (PMID: 25248098) and this finding has not since been replicated. Therefore demoting the gene rating, inline with review by Dmitrijs Rots.
Hereditary ataxia v1.322 DMXL2 Arina Puzriakova Gene: dmxl2 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v4.62 CPA6 John Taylor changed review comment from: The pathology of this gene is predicated on two publications: Salzmann et al. (2012) PubMed: 21922598 and Sapio et al. (2012) PubMed: 23105115. Both of these publications were issued prior to large population-based allele assessments and the evidence for pathogenicity is reliant on circumstantial evidence. None of the variants that form the foundation of this disease link would have sufficient evidence in support pathogenicity using current classification criteria. This gene should be recategorized as having a Red rating.

Evidence against pathogenicity for the reported variants:
Salzmann et al. (2012) proposed haploinsufficiency rather than gain of function; however, there is no obvious constraint score across the length of the gene. Previously reported pathogenic variants are, in some cases (see below), present in gnomAD at allele frequencies contrary to the incidence of the associated condition.

CPA6 p.(Ala270Val) rs114402678 has been reported has a homozygous variant in gnomADv3.1.2 in the non-neuro sub category (only samples that were not collected as part of a neurologic or psychiatric case/control study, or samples collected as part of a neurologic or psychiatric case/control study but designated as controls). The allele frequency and the observed number of homozygotes is not significantly different from the number of expected homozygote alleles based on the Hardy-Weinberg equilibrium.

CPA6(NM_020361.5):c.799G>A p.(Gly267Arg) rs61738009 was reported as a heterozygous pathogenic variant; however, this variant has been reported in >860 heterozygous individuals in gnomADv2.1.1 and v3.1.2.; to: The pathology of this gene is predicated on two publications: Salzmann et al. (2012) PubMed: 21922598 and Sapio et al. (2012) PubMed: 23105115. Both of these publications were issued prior to large population-based allele assessments and the evidence for pathogenicity is reliant on circumstantial evidence. None of the variants that form the foundation of this disease link would have sufficient evidence in support pathogenicity using current classification criteria. This gene should be recategorized as having a Red rating.

Evidence against pathogenicity for the reported variants:
Salzmann et al. (2012) proposed haploinsufficiency rather than gain of function; however, there is no obvious constraint score across the length of the gene. Previously reported pathogenic variants are, in some cases (see below), present in gnomAD at allele frequencies contrary to the incidence of the associated condition.

CPA6 p.(Ala270Val) rs114402678 has been reported has a homozygous variant in gnomADv3.1.2 in the non-neuro sub category (only samples that were not collected as part of a neurologic or psychiatric case/control study, or samples collected as part of a neurologic or psychiatric case/control study but designated as controls). The allele frequency and the observed number of homozygotes is not significantly different from the number of expected homozygote alleles based on the Hardy-Weinberg equilibrium.

CPA6(NM_020361.5):c.799G>A p.(Gly267Arg) rs61738009 was reported as a heterozygous pathogenic variant; however, this variant has been reported in >860 heterozygous individuals in gnomADv2.1.1 and v3.1.2.
Early onset or syndromic epilepsy v4.62 CPA6 John Taylor reviewed gene: CPA6: Rating: RED; Mode of pathogenicity: Other; Publications: PMID:21922598, 23105115; Phenotypes: ; Mode of inheritance: Other
Wiskott-Aldrich syndrome v0.1 WAS Achchuthan Shanmugasundram reviewed gene: WAS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Wilson disease v0.1 ATP7B Achchuthan Shanmugasundram reviewed gene: ATP7B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
von Willebrand disease v0.1 VWF Achchuthan Shanmugasundram reviewed gene: VWF: Rating: GREEN; 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
Von Hippel Lindau syndrome v0.1 VHL Achchuthan Shanmugasundram reviewed gene: VHL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Variegate porphyria v0.1 PPOX Achchuthan Shanmugasundram reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Tuberous sclerosis v0.1 TSC2 Achchuthan Shanmugasundram reviewed gene: TSC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Tuberous sclerosis v0.1 TSC1 Achchuthan Shanmugasundram reviewed gene: TSC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thiamine metabolism dysfunction syndrome 2 v0.1 SLC19A3 Achchuthan Shanmugasundram reviewed gene: SLC19A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thanatophoric dysplasia v0.1 FGFR3 Achchuthan Shanmugasundram reviewed gene: FGFR3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sickle cell, thalassaemia and other haemoglobinopathies v0.1 HBB Achchuthan Shanmugasundram reviewed gene: HBB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sickle cell, thalassaemia and other haemoglobinopathies v0.1 HBA1 Achchuthan Shanmugasundram reviewed gene: HBA1: Rating: GREEN; 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
Tay-Sachs disease v0.1 HEXA Achchuthan Shanmugasundram reviewed gene: HEXA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Syndromic and non syndromic craniosynostosis involving midline sutures v0.1 SMAD6 Achchuthan Shanmugasundram changed review comment from: SMAD6 has been added to the panel for R416 Syndromic and non syndromic craniosynostosis involving midline sutures only with a green rating as agreed with the NHS Genomic Medicine Service.; to: SMAD6 has been added to the panel for R416 Syndromic and non syndromic craniosynostosis involving midline sutures with a green rating as agreed with the NHS Genomic Medicine Service.
Syndromic and non syndromic craniosynostosis involving midline sutures v0.1 SMAD6 Achchuthan Shanmugasundram reviewed gene: SMAD6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Subcutaneous panniculitis T-cell lymphoma (SPTCL) v0.1 HAVCR2 Achchuthan Shanmugasundram reviewed gene: HAVCR2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Spinal muscular atrophy type 1 rare mutation testing v0.1 SMN1 Achchuthan Shanmugasundram reviewed gene: SMN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Smith-Lemli-Opitz syndrome v0.1 DHCR7 Achchuthan Shanmugasundram reviewed gene: DHCR7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Sitosterolaemia v0.1 ABCG8 Achchuthan Shanmugasundram reviewed gene: ABCG8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Sitosterolaemia v0.1 ABCG5 Achchuthan Shanmugasundram reviewed gene: ABCG5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Short stature - SHOX deficiency v0.1 SHOX Achchuthan Shanmugasundram reviewed gene: SHOX: Rating: GREEN; 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
Severe combined immunodeficiency with PNP deficiency v0.1 PNP Achchuthan Shanmugasundram reviewed gene: PNP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe combined immunodeficiency with adenosine deaminase deficiency v0.1 ADA Achchuthan Shanmugasundram reviewed gene: ADA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Segmental or atypical neurofibromatosis type 1 testing v0.1 NF1 Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
SCID with features of gamma chain deficiency v0.1 IL2RG Achchuthan Shanmugasundram reviewed gene: IL2RG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sandhoff disease v0.1 HEXB Achchuthan Shanmugasundram reviewed gene: HEXB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinoblastoma v0.1 RB1 Achchuthan Shanmugasundram reviewed gene: RB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pulmonary alveolar microlithiasis v0.1 SLC34A2 Achchuthan Shanmugasundram reviewed gene: SLC34A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
PTEN Hamartoma Tumour Syndrome v0.1 PTEN Achchuthan Shanmugasundram reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudoxanthoma elasticum v0.1 ENPP1 Achchuthan Shanmugasundram reviewed gene: ENPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pseudoxanthoma elasticum v0.1 ABCC6 Achchuthan Shanmugasundram reviewed gene: ABCC6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary hyperaldosteronism - KCNJ5 v0.1 KCNJ5 Achchuthan Shanmugasundram reviewed gene: KCNJ5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
POLG-related disorder v0.1 POLG Achchuthan Shanmugasundram reviewed gene: POLG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenylketonuria v0.1 PAH Achchuthan Shanmugasundram reviewed gene: PAH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Peutz Jeghers Syndrome v0.1 STK11 Achchuthan Shanmugasundram reviewed gene: STK11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Nijmegen breakage syndrome v0.1 NBN Achchuthan Shanmugasundram reviewed gene: NBN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Niemann-Pick disease type A or B v0.1 SMPD1 Achchuthan Shanmugasundram reviewed gene: SMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Niemann Pick disease type C v0.1 NPC2 Achchuthan Shanmugasundram reviewed gene: NPC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Niemann Pick disease type C v0.1 NPC1 Achchuthan Shanmugasundram reviewed gene: NPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v0.1 SUFU Achchuthan Shanmugasundram reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v0.1 PTCH1 Achchuthan Shanmugasundram reviewed gene: PTCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neutropaenia consistent with ELANE mutations v0.1 ELANE Achchuthan Shanmugasundram reviewed gene: ELANE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neuronal ceroid lipofuscinosis type 2 v0.1 TPP1 Achchuthan Shanmugasundram Deleted their comment
Neuronal ceroid lipofuscinosis type 2 v0.1 TPP1 Achchuthan Shanmugasundram changed review comment from: TPP1 has been added to the panel for R271 Neuronal ceroid lipofuscinosis type 2 with a green rating as agreed with the NHS Genomic Medicine Service.; to: TPP1 has been added to the panel for R271 Neuronal ceroid lipofuscinosis type 2 with a green rating as agreed with the NHS Genomic Medicine Service.
Neuronal ceroid lipofuscinosis type 2 v0.1 TPP1 Achchuthan Shanmugasundram commented on gene: TPP1: TPP1 has been added to the panel for R271 Neuronal ceroid lipofuscinosis type 2 with a green rating as agreed with the NHS Genomic Medicine Service.
Neuronal ceroid lipofuscinosis type 2 v0.1 TPP1 Achchuthan Shanmugasundram reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neurofibromatosis type 1 (GMS) v0.1 SPRED1 Achchuthan Shanmugasundram reviewed gene: SPRED1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurofibromatosis type 1 (GMS) v0.1 NF1 Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes - small panel v0.1 KCNJ11 Achchuthan Shanmugasundram reviewed gene: KCNJ11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes - small panel v0.1 ABCC8 Achchuthan Shanmugasundram reviewed gene: ABCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
NARP syndrome or maternally inherited Leigh syndrome v0.1 MT-ND6 Achchuthan Shanmugasundram reviewed gene: MT-ND6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
NARP syndrome or maternally inherited Leigh syndrome v0.1 MT-ATP6 Achchuthan Shanmugasundram reviewed gene: MT-ATP6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Multiple exostoses v0.1 EXT2 Achchuthan Shanmugasundram reviewed gene: EXT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Multiple exostoses v0.1 EXT1 Achchuthan Shanmugasundram reviewed gene: EXT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Multiple endocrine neoplasia type 2 v0.1 RET Achchuthan Shanmugasundram reviewed gene: RET: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mucopolysaccharidosis type VI v0.1 ARSB Achchuthan Shanmugasundram reviewed gene: ARSB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mucopolysaccharidosis type IVA v0.1 GALNS Achchuthan Shanmugasundram reviewed gene: GALNS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mucopolysaccharidosis type IIIB v0.1 NAGLU Achchuthan Shanmugasundram reviewed gene: NAGLU: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mucopolysaccharidosis type IIIA v0.2 SGSH Achchuthan Shanmugasundram reviewed gene: SGSH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mucopolysaccharidosis type II v0.1 IDS Achchuthan Shanmugasundram reviewed gene: IDS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mucopolysaccharidosis type IH or S v0.1 IDUA Achchuthan Shanmugasundram reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mucolipidosis II and III Alpha or Beta v0.1 GNPTAB Achchuthan Shanmugasundram reviewed gene: GNPTAB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monitoring for G(M)CSF escape mutations v0.1 CSF3R Achchuthan Shanmugasundram reviewed gene: CSF3R: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial neurogastrointestinal encephalopathy v0.1 TYMP Achchuthan Shanmugasundram reviewed gene: TYMP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial Complex V deficiency, TMEM70 type v0.1 TMEM70 Achchuthan Shanmugasundram reviewed gene: TMEM70: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Lysosomal acid lipase deficiency v0.1 LIPA Achchuthan Shanmugasundram reviewed gene: LIPA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Lymphoproliferative syndrome with absent SAP expression v0.1 SH2D1A Achchuthan Shanmugasundram reviewed gene: SH2D1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Krabbe disease - Saposin A deficiency v0.1 PSAP Achchuthan Shanmugasundram reviewed gene: PSAP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Krabbe disease - GALC deficiency v0.1 GALC Achchuthan Shanmugasundram reviewed gene: GALC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v0.1 FOXP3 Achchuthan Shanmugasundram reviewed gene: FOXP3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v0.1 PAX5 Achchuthan Shanmugasundram reviewed gene: PAX5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v0.1 ETV6 Achchuthan Shanmugasundram reviewed gene: ETV6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inherited parathyroid cancer v0.1 CDC73 Achchuthan Shanmugasundram reviewed gene: CDC73: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Incontinentia pigmenti v0.1 IKBKG Achchuthan Shanmugasundram reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Hereditary angioedema types I and II v0.1 SERPING1 Achchuthan Shanmugasundram reviewed gene: SERPING1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Haemophagocytic syndrome with absent XIAP expression v0.1 XIAP Achchuthan Shanmugasundram reviewed gene: XIAP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Haemophagocytic syndrome with absent perforin expression v0.1 PRF1 Achchuthan Shanmugasundram reviewed gene: PRF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v0.1 HBB Achchuthan Shanmugasundram reviewed gene: HBB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v0.1 HBA1 Achchuthan Shanmugasundram reviewed gene: HBA1: Rating: GREEN; 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
GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v0.1 GLB1 Achchuthan Shanmugasundram reviewed gene: GLB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Glycogen storage disease V v0.1 PYGM Achchuthan Shanmugasundram reviewed gene: PYGM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Glucokinase-related fasting hyperglycaemia v0.1 GCK Achchuthan Shanmugasundram reviewed gene: GCK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Generalised arterial calcification in infancy v0.1 ENPP1 Achchuthan Shanmugasundram reviewed gene: ENPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Generalised arterial calcification in infancy v0.1 ABCC6 Achchuthan Shanmugasundram reviewed gene: ABCC6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Gaucher disease v0.1 GBA Achchuthan Shanmugasundram reviewed gene: GBA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fumarate hydratase-related tumour syndromes v0.1 FH Achchuthan Shanmugasundram reviewed gene: FH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 SUFU Achchuthan Shanmugasundram reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 SMARCE1 Achchuthan Shanmugasundram reviewed gene: SMARCE1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 SMARCB1 Achchuthan Shanmugasundram reviewed gene: SMARCB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 NF2 Achchuthan Shanmugasundram reviewed gene: NF2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 LZTFL1 Achchuthan Shanmugasundram reviewed gene: LZTFL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 DGCR8 Achchuthan Shanmugasundram reviewed gene: DGCR8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial dysalbuminaemic hyperthyroxinaemia v0.1 ALB Achchuthan Shanmugasundram reviewed gene: ALB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Factor XIII deficiency v0.1 F13B Achchuthan Shanmugasundram reviewed gene: F13B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Factor XIII deficiency v0.1 F13A1 Achchuthan Shanmugasundram reviewed gene: F13A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Factor XI deficiency v0.1 F11 Achchuthan Shanmugasundram reviewed gene: F11: Rating: GREEN; 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
Factor X deficiency v0.1 F10 Achchuthan Shanmugasundram Deleted their comment
Factor X deficiency v0.1 F10 Achchuthan Shanmugasundram commented on gene: F10: F10 has been added to the panel for R119 Factor X deficiency with a green rating as agreed with the NHS Genomic Medicine Service.
Factor X deficiency v0.1 F10 Achchuthan Shanmugasundram reviewed gene: F10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Factor VIII deficiency v0.1 F8 Achchuthan Shanmugasundram reviewed gene: F8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Factor VII deficiency v0.1 F7 Achchuthan Shanmugasundram reviewed gene: F7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Factor V deficiency v0.1 F5 Achchuthan Shanmugasundram reviewed gene: F5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Factor IX deficiency v0.1 F9 Achchuthan Shanmugasundram reviewed gene: F9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Factor II deficiency v0.1 F2 Achchuthan Shanmugasundram reviewed gene: F2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Facioscapulohumeral muscular dystrophy - extended testing v0.1 SMCHD1 Achchuthan Shanmugasundram reviewed gene: SMCHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fabry disease v0.1 GLA Achchuthan Shanmugasundram reviewed gene: GLA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Elastin-related phenotypes v0.1 ELN Achchuthan Shanmugasundram reviewed gene: ELN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Duchenne or Becker muscular dystrophy v0.1 DMD Achchuthan Shanmugasundram reviewed gene: DMD: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
DICER1-related cancer predisposition v0.1 DICER1 Achchuthan Shanmugasundram reviewed gene: DICER1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cystinosis v0.1 CTNS Achchuthan Shanmugasundram reviewed gene: CTNS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cystic fibrosis diagnostic test v0.1 CFTR Achchuthan Shanmugasundram edited their review of gene: CFTR: Changed rating: GREEN
Cystic fibrosis diagnostic test v0.1 CFTR Achchuthan Shanmugasundram reviewed gene: CFTR: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital adrenal hyperplasia diagnostic test v0.1 CYP21A2 Achchuthan Shanmugasundram reviewed gene: CYP21A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined vitamin K-dependent clotting factor deficiency v0.1 VKORC1 Achchuthan Shanmugasundram reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined vitamin K-dependent clotting factor deficiency v0.1 GGCX Achchuthan Shanmugasundram reviewed gene: GGCX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Central congenital hypoventilation v0.1 PHOX2B Achchuthan Shanmugasundram reviewed gene: PHOX2B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Carney complex v0.1 PRKAR1A Achchuthan Shanmugasundram reviewed gene: PRKAR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Calcium-sensing receptor phenotypes v0.1 CASR Achchuthan Shanmugasundram reviewed gene: CASR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
CADASIL v0.1 NOTCH3 Achchuthan Shanmugasundram reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Blepharophimosis ptosis and epicanthus inversus v0.1 FOXL2 Achchuthan Shanmugasundram reviewed gene: FOXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Beckwith-Wiedemann syndrome v0.1 CDKN1C Achchuthan Shanmugasundram reviewed gene: CDKN1C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Barth syndrome v0.1 TAZ Achchuthan Shanmugasundram reviewed gene: TAZ: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
BAP1 associated tumour predisposition syndrome v0.2 BAP1 Achchuthan Shanmugasundram reviewed gene: BAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Autoimmune Polyendocrine Syndrome v0.2 AIRE Achchuthan Shanmugasundram edited their review of gene: AIRE: Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Autoimmune Polyendocrine Syndrome v0.2 AIRE Achchuthan Shanmugasundram commented on gene: AIRE
von Willebrand disease v0.1 VWF Achchuthan Shanmugasundram gene: VWF was added
gene: VWF was added to von Willebrand disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: VWF was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Wiskott-Aldrich syndrome v0.1 WAS Achchuthan Shanmugasundram gene: WAS was added
gene: WAS was added to Wiskott-Aldrich syndrome. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: WAS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Wilson disease v0.1 ATP7B Achchuthan Shanmugasundram gene: ATP7B was added
gene: ATP7B was added to Wilson disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ATP7B was set to BIALLELIC, autosomal or pseudoautosomal
Von Hippel Lindau syndrome v0.1 VHL Achchuthan Shanmugasundram gene: VHL was added
gene: VHL was added to Von Hippel Lindau syndrome. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: VHL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Variegate porphyria v0.1 PPOX Achchuthan Shanmugasundram gene: PPOX was added
gene: PPOX was added to Variegate porphyria. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: PPOX was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Tuberous sclerosis v0.1 TSC2 Achchuthan Shanmugasundram gene: TSC2 was added
gene: TSC2 was added to Tuberous sclerosis. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TSC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Tuberous sclerosis v0.1 TSC1 Achchuthan Shanmugasundram gene: TSC1 was added
gene: TSC1 was added to Tuberous sclerosis. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TSC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thiamine metabolism dysfunction syndrome 2 v0.1 SLC19A3 Achchuthan Shanmugasundram gene: SLC19A3 was added
gene: SLC19A3 was added to Thiamine metabolism dysfunction syndrome 2. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: SLC19A3 was set to BIALLELIC, autosomal or pseudoautosomal
Thanatophoric dysplasia v0.1 FGFR3 Achchuthan Shanmugasundram gene: FGFR3 was added
gene: FGFR3 was added to Thanatophoric dysplasia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FGFR3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sickle cell, thalassaemia and other haemoglobinopathies v0.1 HBB Achchuthan Shanmugasundram gene: HBB was added
gene: HBB was added to Thalassaemia and other haemoglobinopathies. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: HBB was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sickle cell, thalassaemia and other haemoglobinopathies v0.1 HBA1 Achchuthan Shanmugasundram gene: HBA1 was added
gene: HBA1 was added to Thalassaemia and other haemoglobinopathies. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: HBA1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Tay-Sachs disease v0.1 HEXA Achchuthan Shanmugasundram gene: HEXA was added
gene: HEXA was added to Tay-Sachs disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: HEXA was set to BIALLELIC, autosomal or pseudoautosomal
Syndromic and non syndromic craniosynostosis involving midline sutures v0.1 SMAD6 Achchuthan Shanmugasundram gene: SMAD6 was added
gene: SMAD6 was added to Syndromic and non syndromic craniosynostosis involving midline sutures. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: SMAD6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Subcutaneous panniculitis T-cell lymphoma (SPTCL) v0.1 HAVCR2 Achchuthan Shanmugasundram gene: HAVCR2 was added
gene: HAVCR2 was added to Subcutaneous panniculitis T-cell lymphoma (SPTCL). Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: HAVCR2 was set to BIALLELIC, autosomal or pseudoautosomal
Spinal muscular atrophy type 1 rare mutation testing v0.1 SMN1 Achchuthan Shanmugasundram gene: SMN1 was added
gene: SMN1 was added to Spinal muscular atrophy type 1 rare mutation testing. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SMN1 was set to BIALLELIC, autosomal or pseudoautosomal
Smith-Lemli-Opitz syndrome v0.1 DHCR7 Achchuthan Shanmugasundram gene: DHCR7 was added
gene: DHCR7 was added to Smith-Lemli-Opitz syndrome. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: DHCR7 was set to BIALLELIC, autosomal or pseudoautosomal
Sitosterolaemia v0.1 ABCG8 Achchuthan Shanmugasundram gene: ABCG8 was added
gene: ABCG8 was added to Sitosterolaemia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ABCG8 was set to BIALLELIC, autosomal or pseudoautosomal
Sitosterolaemia v0.1 ABCG5 Achchuthan Shanmugasundram gene: ABCG5 was added
gene: ABCG5 was added to Sitosterolaemia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ABCG5 was set to BIALLELIC, autosomal or pseudoautosomal
Short stature - SHOX deficiency v0.1 SHOX Achchuthan Shanmugasundram gene: SHOX was added
gene: SHOX was added to Short stature - SHOX deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: SHOX was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Severe combined immunodeficiency with PNP deficiency v0.1 PNP Achchuthan Shanmugasundram gene: PNP was added
gene: PNP was added to Severe combined immunodeficiency with PNP deficiency. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PNP was set to BIALLELIC, autosomal or pseudoautosomal
Severe combined immunodeficiency with adenosine deaminase deficiency v0.1 ADA Achchuthan Shanmugasundram gene: ADA was added
gene: ADA was added to Severe combined immunodeficiency with adenosine deaminase deficiency. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ADA was set to BIALLELIC, autosomal or pseudoautosomal
Segmental or atypical neurofibromatosis type 1 testing v0.1 NF1 Achchuthan Shanmugasundram gene: NF1 was added
gene: NF1 was added to Segmental or atypical neurofibromatosis type 1 testing. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: NF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
SCID with features of gamma chain deficiency v0.1 IL2RG Achchuthan Shanmugasundram gene: IL2RG was added
gene: IL2RG was added to SCID with features of gamma chain deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: IL2RG was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sandhoff disease v0.1 HEXB Achchuthan Shanmugasundram gene: HEXB was added
gene: HEXB was added to Sandhoff disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: HEXB was set to BIALLELIC, autosomal or pseudoautosomal
Retinoblastoma v0.1 RB1 Achchuthan Shanmugasundram gene: RB1 was added
gene: RB1 was added to Retinoblastoma. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: RB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenylketonuria v0.1 PAH Achchuthan Shanmugasundram gene: PAH was added
gene: PAH was added to Phenylketonuria. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: PAH was set to BIALLELIC, autosomal or pseudoautosomal
Pulmonary alveolar microlithiasis v0.1 SLC34A2 Achchuthan Shanmugasundram gene: SLC34A2 was added
gene: SLC34A2 was added to Pulmonary alveolar microlithiasis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: SLC34A2 was set to BIALLELIC, autosomal or pseudoautosomal
PTEN Hamartoma Tumour Syndrome v0.1 PTEN Achchuthan Shanmugasundram gene: PTEN was added
gene: PTEN was added to PTEN Hamartoma Tumor Syndrome. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: PTEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pseudoxanthoma elasticum v0.1 ENPP1 Achchuthan Shanmugasundram gene: ENPP1 was added
gene: ENPP1 was added to Pseudoxanthoma elasticum. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: ENPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Pseudoxanthoma elasticum v0.1 ABCC6 Achchuthan Shanmugasundram gene: ABCC6 was added
gene: ABCC6 was added to Pseudoxanthoma elasticum. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: ABCC6 was set to BIALLELIC, autosomal or pseudoautosomal
Primary hyperaldosteronism - KCNJ5 v0.1 KCNJ5 Achchuthan Shanmugasundram gene: KCNJ5 was added
gene: KCNJ5 was added to Primary hyperaldosteronism - KCNJ5. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: KCNJ5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
POLG-related disorder v0.1 POLG Achchuthan Shanmugasundram gene: POLG was added
gene: POLG was added to POLG-related disorder. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: POLG was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Peutz Jeghers Syndrome v0.1 STK11 Achchuthan Shanmugasundram gene: STK11 was added
gene: STK11 was added to Peutz Jeghers Syndrome. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: STK11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v0.1 SUFU Achchuthan Shanmugasundram gene: SUFU was added
gene: SUFU was added to Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SUFU was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v0.1 PTCH1 Achchuthan Shanmugasundram gene: PTCH1 was added
gene: PTCH1 was added to Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Nijmegen breakage syndrome v0.1 NBN Achchuthan Shanmugasundram gene: NBN was added
gene: NBN was added to Nijmegen breakage syndrome. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: NBN was set to BIALLELIC, autosomal or pseudoautosomal
Niemann-Pick disease type A or B v0.1 SMPD1 Achchuthan Shanmugasundram gene: SMPD1 was added
gene: SMPD1 was added to Niemann-Pick disease type A or B. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: SMPD1 was set to BIALLELIC, autosomal or pseudoautosomal
Niemann Pick disease type C v0.1 NPC2 Achchuthan Shanmugasundram gene: NPC2 was added
gene: NPC2 was added to Niemann Pick disease type C. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NPC2 was set to BIALLELIC, autosomal or pseudoautosomal
Niemann Pick disease type C v0.1 NPC1 Achchuthan Shanmugasundram gene: NPC1 was added
gene: NPC1 was added to Niemann Pick disease type C. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NPC1 was set to BIALLELIC, autosomal or pseudoautosomal
Neutropaenia consistent with ELANE mutations v0.1 ELANE Achchuthan Shanmugasundram gene: ELANE was added
gene: ELANE was added to Neutropaenia consistent with ELANE mutations. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: ELANE was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neuronal ceroid lipofuscinosis type 2 v0.1 TPP1 Achchuthan Shanmugasundram gene: TPP1 was added
gene: TPP1 was added to Neuronal ceroid lipofuscinosis type 2. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Neurofibromatosis type 1 (GMS) v0.1 SPRED1 Achchuthan Shanmugasundram gene: SPRED1 was added
gene: SPRED1 was added to Neurofibromatosis type 1 (GMS). Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SPRED1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurofibromatosis type 1 (GMS) v0.1 NF1 Achchuthan Shanmugasundram gene: NF1 was added
gene: NF1 was added to Neurofibromatosis type 1 (GMS). Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes - small panel v0.1 KCNJ11 Achchuthan Shanmugasundram gene: KCNJ11 was added
gene: KCNJ11 was added to Neonatal diabetes - small panel. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: KCNJ11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes - small panel v0.1 ABCC8 Achchuthan Shanmugasundram gene: ABCC8 was added
gene: ABCC8 was added to Neonatal diabetes - small panel. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ABCC8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
NARP syndrome or maternally inherited Leigh syndrome v0.1 MT-ND6 Achchuthan Shanmugasundram gene: MT-ND6 was added
gene: MT-ND6 was added to NARP syndrome or maternally inherited Leigh syndrome. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene gene: MT-ND6 was set to MITOCHONDRIAL
NARP syndrome or maternally inherited Leigh syndrome v0.1 MT-ATP6 Achchuthan Shanmugasundram gene: MT-ATP6 was added
gene: MT-ATP6 was added to NARP syndrome or maternally inherited Leigh syndrome. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene gene: MT-ATP6 was set to MITOCHONDRIAL
Multiple exostoses v0.1 EXT2 Achchuthan Shanmugasundram gene: EXT2 was added
gene: EXT2 was added to Multiple exostoses. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: EXT2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Multiple exostoses v0.1 EXT1 Achchuthan Shanmugasundram gene: EXT1 was added
gene: EXT1 was added to Multiple exostoses. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: EXT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Multiple endocrine neoplasia type 2 v0.1 RET Achchuthan Shanmugasundram gene: RET was added
gene: RET was added to Multiple endocrine neoplasia type 2. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: RET was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mucopolysaccharidosis type II v0.1 IDS Achchuthan Shanmugasundram gene: IDS was added
gene: IDS was added to Mucopolysaccharidosis type II. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: IDS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mucopolysaccharidosis type VI v0.1 ARSB Achchuthan Shanmugasundram gene: ARSB was added
gene: ARSB was added to Mucopolysaccharidosis type VI. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: ARSB was set to BIALLELIC, autosomal or pseudoautosomal
Mucopolysaccharidosis type IVA v0.1 GALNS Achchuthan Shanmugasundram gene: GALNS was added
gene: GALNS was added to Mucopolysaccharidosis type IVA. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: GALNS was set to BIALLELIC, autosomal or pseudoautosomal
Mucopolysaccharidosis type IIIB v0.1 NAGLU Achchuthan Shanmugasundram gene: NAGLU was added
gene: NAGLU was added to Mucopolysaccharidosis type IIIB. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NAGLU was set to BIALLELIC, autosomal or pseudoautosomal
Mucopolysaccharidosis type IIIA v0.1 SGSH Achchuthan Shanmugasundram gene: SGSH was added
gene: SGSH was added to Mucopolysaccharidosis type IIIA. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SGSH was set to BIALLELIC, autosomal or pseudoautosomal
Mucopolysaccharidosis type IH or S v0.1 IDUA Achchuthan Shanmugasundram gene: IDUA was added
gene: IDUA was added to Mucopolysaccharidosis type IH/S. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: IDUA was set to BIALLELIC, autosomal or pseudoautosomal
Mucolipidosis II and III Alpha or Beta v0.1 GNPTAB Achchuthan Shanmugasundram gene: GNPTAB was added
gene: GNPTAB was added to Mucolipidosis II and III Alpha/Beta. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: GNPTAB was set to BIALLELIC, autosomal or pseudoautosomal
Monitoring for G(M)CSF escape mutations v0.1 CSF3R Achchuthan Shanmugasundram gene: CSF3R was added
gene: CSF3R was added to Monitoring for G(M)CSF escape mutations. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CSF3R was set to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial neurogastrointestinal encephalopathy v0.1 TYMP Achchuthan Shanmugasundram gene: TYMP was added
gene: TYMP was added to Mitochondrial neurogastrointestinal encephalopathy. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TYMP was set to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial Complex V deficiency, TMEM70 type v0.1 TMEM70 Achchuthan Shanmugasundram gene: TMEM70 was added
gene: TMEM70 was added to Mitochondrial Complex V deficiency, TMEM70 type. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TMEM70 was set to BIALLELIC, autosomal or pseudoautosomal
Lysosomal acid lipase deficiency v0.1 LIPA Achchuthan Shanmugasundram gene: LIPA was added
gene: LIPA was added to Lysosomal acid lipase deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: LIPA was set to BIALLELIC, autosomal or pseudoautosomal
Lymphoproliferative syndrome with absent SAP expression v0.1 SH2D1A Achchuthan Shanmugasundram gene: SH2D1A was added
gene: SH2D1A was added to Lymphoproliferative syndrome with absent SAP expression. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SH2D1A was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Krabbe disease - Saposin A deficiency v0.1 PSAP Achchuthan Shanmugasundram gene: PSAP was added
gene: PSAP was added to Krabbe disease - Saposin A deficiency. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PSAP was set to BIALLELIC, autosomal or pseudoautosomal
Krabbe disease - GALC deficiency v0.1 GALC Achchuthan Shanmugasundram gene: GALC was added
gene: GALC was added to Krabbe disease - GALC deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: GALC was set to BIALLELIC, autosomal or pseudoautosomal
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v0.1 PAX5 Achchuthan Shanmugasundram gene: PAX5 was added
gene: PAX5 was added to Inherited susceptibility to acute lymphoblastoid leukaemia (ALL). Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PAX5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v0.1 ETV6 Achchuthan Shanmugasundram gene: ETV6 was added
gene: ETV6 was added to Inherited susceptibility to acute lymphoblastoid leukaemia (ALL). Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ETV6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Adult onset neurodegenerative disorder v4.28 FXN_GAA Sarah Leigh Tag Q3_23_promote_green tag was added to STR: FXN_GAA.
Adult onset neurodegenerative disorder v4.28 FXN_GAA Sarah Leigh edited their review of STR: FXN_GAA: Added comment: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.; Changed rating: GREEN
IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v0.1 FOXP3 Achchuthan Shanmugasundram gene: FOXP3 was added
gene: FOXP3 was added to IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: FOXP3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Inherited parathyroid cancer v0.1 CDC73 Achchuthan Shanmugasundram gene: CDC73 was added
gene: CDC73 was added to Inherited parathyroid cancer. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CDC73 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inherited breast cancer and ovarian cancer v2.7 RAD51D Achchuthan Shanmugasundram Source NHS GMS was added to RAD51D.
Inherited breast cancer and ovarian cancer v2.7 RAD51C Achchuthan Shanmugasundram Source NHS GMS was added to RAD51C.
Incontinentia pigmenti v0.1 IKBKG Achchuthan Shanmugasundram gene: IKBKG was added
gene: IKBKG was added to Incontinentia pigmenti. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: IKBKG was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Hereditary angioedema types I and II v0.1 SERPING1 Achchuthan Shanmugasundram gene: SERPING1 was added
gene: SERPING1 was added to Hereditary angioedema types I and II. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: SERPING1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Haemophagocytic syndrome with absent XIAP expression v0.1 XIAP Achchuthan Shanmugasundram gene: XIAP was added
gene: XIAP was added to Haemophagocytic syndrome with absent XIAP expression. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: XIAP was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Haemophagocytic syndrome with absent perforin expression v0.1 PRF1 Achchuthan Shanmugasundram gene: PRF1 was added
gene: PRF1 was added to Haemophagocytic syndrome with absent perforin expression. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PRF1 was set to BIALLELIC, autosomal or pseudoautosomal
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v0.1 HBB Achchuthan Shanmugasundram gene: HBB was added
gene: HBB was added to Haemoglobinopathy trait or carrier testing. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: HBB was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v0.1 HBA1 Achchuthan Shanmugasundram gene: HBA1 was added
gene: HBA1 was added to Haemoglobinopathy trait or carrier testing. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: HBA1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v0.1 GLB1 Achchuthan Shanmugasundram gene: GLB1 was added
gene: GLB1 was added to GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: GLB1 was set to BIALLELIC, autosomal or pseudoautosomal
Glycogen storage disease V v0.1 PYGM Achchuthan Shanmugasundram gene: PYGM was added
gene: PYGM was added to Glycogen storage disease V. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: PYGM was set to BIALLELIC, autosomal or pseudoautosomal
Glucokinase-related fasting hyperglycaemia v0.1 GCK Achchuthan Shanmugasundram gene: GCK was added
gene: GCK was added to Glucokinase-related fasting hyperglycaemia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: GCK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Generalised arterial calcification in infancy v0.1 ENPP1 Achchuthan Shanmugasundram gene: ENPP1 was added
gene: ENPP1 was added to Generalised arterial calcification in infancy. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ENPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Generalised arterial calcification in infancy v0.1 ABCC6 Achchuthan Shanmugasundram gene: ABCC6 was added
gene: ABCC6 was added to Generalised arterial calcification in infancy. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ABCC6 was set to BIALLELIC, autosomal or pseudoautosomal
Gaucher disease v0.1 GBA Achchuthan Shanmugasundram gene: GBA was added
gene: GBA was added to Gaucher disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: GBA was set to BIALLELIC, autosomal or pseudoautosomal
Fumarate hydratase-related tumour syndromes v0.1 FH Achchuthan Shanmugasundram gene: FH was added
gene: FH was added to Fumarate hydratase-related tumour syndromes. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FH was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 SUFU Achchuthan Shanmugasundram gene: SUFU was added
gene: SUFU was added to Familial tumours of the nervous system. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SUFU was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 SMARCE1 Achchuthan Shanmugasundram gene: SMARCE1 was added
gene: SMARCE1 was added to Familial tumours of the nervous system. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SMARCE1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 SMARCB1 Achchuthan Shanmugasundram gene: SMARCB1 was added
gene: SMARCB1 was added to Familial tumours of the nervous system. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SMARCB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 NF2 Achchuthan Shanmugasundram gene: NF2 was added
gene: NF2 was added to Familial tumours of the nervous system. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 LZTFL1 Achchuthan Shanmugasundram gene: LZTFL1 was added
gene: LZTFL1 was added to Familial tumours of the nervous system. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: LZTFL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Familial tumours of the nervous system v0.1 DGCR8 Achchuthan Shanmugasundram gene: DGCR8 was added
gene: DGCR8 was added to Familial tumours of the nervous system. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: DGCR8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Adult onset hereditary spastic paraplegia v3.10 ATXN10_ATTCT Sarah Leigh Tag Q3_23_promote_green tag was added to STR: ATXN10_ATTCT.
Familial dysalbuminaemic hyperthyroxinaemia v0.1 ALB Achchuthan Shanmugasundram gene: ALB was added
gene: ALB was added to Familial dysalbuminaemic hyperthyroxinaemia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ALB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Adult onset hereditary spastic paraplegia v3.10 ATXN10_ATTCT Sarah Leigh reviewed STR: ATXN10_ATTCT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Factor XIII deficiency v0.1 F13B Achchuthan Shanmugasundram gene: F13B was added
gene: F13B was added to Factor XIII deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: F13B was set to BIALLELIC, autosomal or pseudoautosomal
Factor XIII deficiency v0.1 F13A1 Achchuthan Shanmugasundram gene: F13A1 was added
gene: F13A1 was added to Factor XIII deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: F13A1 was set to BIALLELIC, autosomal or pseudoautosomal
Adult onset dystonia, chorea or related movement disorder v3.4 PPP2R2B_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: PPP2R2B_CAG.
Factor XI deficiency v0.1 F11 Achchuthan Shanmugasundram gene: F11 was added
gene: F11 was added to Factor XI deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: F11 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Adult onset dystonia, chorea or related movement disorder v3.4 CACNA1A_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: CACNA1A_CAG.
Factor X deficiency v0.1 F10 Achchuthan Shanmugasundram gene: F10 was added
gene: F10 was added to Factor X deficiency. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: F10 was set to BIALLELIC, autosomal or pseudoautosomal
Adult onset dystonia, chorea or related movement disorder v3.4 ATXN3_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: ATXN3_CAG.
Factor VIII deficiency v0.1 F8 Achchuthan Shanmugasundram gene: F8 was added
gene: F8 was added to Factor VIII deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: F8 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Adult onset dystonia, chorea or related movement disorder v3.4 ATXN2_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: ATXN2_CAG.
Factor VII deficiency v0.1 F7 Achchuthan Shanmugasundram gene: F7 was added
gene: F7 was added to Factor VII deficiency. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: F7 was set to BIALLELIC, autosomal or pseudoautosomal
Adult onset dystonia, chorea or related movement disorder v3.4 ATXN1_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: ATXN1_CAG.
Adult onset dystonia, chorea or related movement disorder v3.4 CSTB_CCCCGCCCCGCG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: CSTB_CCCCGCCCCGCG.
Adult onset dystonia, chorea or related movement disorder v3.4 PPP2R2B_CAG Sarah Leigh reviewed STR: PPP2R2B_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset dystonia, chorea or related movement disorder v3.4 CACNA1A_CAG Sarah Leigh reviewed STR: CACNA1A_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Factor V deficiency v0.1 F5 Achchuthan Shanmugasundram gene: F5 was added
gene: F5 was added to Factor V deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: F5 was set to BIALLELIC, autosomal or pseudoautosomal
Adult onset dystonia, chorea or related movement disorder v3.4 ATXN3_CAG Sarah Leigh reviewed STR: ATXN3_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Factor IX deficiency v0.1 F9 Achchuthan Shanmugasundram gene: F9 was added
gene: F9 was added to Factor IX deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: F9 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Adult onset dystonia, chorea or related movement disorder v3.4 ATXN2_CAG Sarah Leigh reviewed STR: ATXN2_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Factor II deficiency v0.1 F2 Achchuthan Shanmugasundram gene: F2 was added
gene: F2 was added to Factor II deficiency. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: F2 was set to BIALLELIC, autosomal or pseudoautosomal
Adult onset dystonia, chorea or related movement disorder v3.4 ATXN1_CAG Sarah Leigh reviewed STR: ATXN1_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset dystonia, chorea or related movement disorder v3.4 CSTB_CCCCGCCCCGCG Sarah Leigh edited their review of STR: CSTB_CCCCGCCCCGCG: Added comment: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.; Changed rating: GREEN
Facioscapulohumeral muscular dystrophy - extended testing v0.1 SMCHD1 Achchuthan Shanmugasundram gene: SMCHD1 was added
gene: SMCHD1 was added to Facioscapulohumeral muscular dystrophy - extended testing. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: SMCHD1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fabry disease v0.1 GLA Achchuthan Shanmugasundram gene: GLA was added
gene: GLA was added to Fabry disease. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: GLA was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Elastin-related phenotypes v0.1 ELN Achchuthan Shanmugasundram gene: ELN was added
gene: ELN was added to Elastin-related phenotypes. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: ELN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Duchenne or Becker muscular dystrophy v0.1 DMD Achchuthan Shanmugasundram gene: DMD was added
gene: DMD was added to Duchenne or Becker muscular dystrophy. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: DMD was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
DICER1-related cancer predisposition v0.1 DICER1 Achchuthan Shanmugasundram gene: DICER1 was added
gene: DICER1 was added to DICER1-related cancer predisposition. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult onset neurodegenerative disorder v4.28 NOP56_GGCCTG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: NOP56_GGCCTG.
Adult onset neurodegenerative disorder v4.28 PPP2R2B_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: PPP2R2B_CAG.
Adult onset neurodegenerative disorder v4.28 CSTB_CCCCGCCCCGCG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: CSTB_CCCCGCCCCGCG.
Adult onset neurodegenerative disorder v4.28 CACNA1A_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: CACNA1A_CAG.
Adult onset neurodegenerative disorder v4.28 ATXN7_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: ATXN7_CAG.
Adult onset neurodegenerative disorder v4.28 ATXN3_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: ATXN3_CAG.
Adult onset neurodegenerative disorder v4.28 ATXN2_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: ATXN2_CAG.
Adult onset neurodegenerative disorder v4.28 ATXN1_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: ATXN1_CAG.
Adult onset neurodegenerative disorder v4.28 ATXN10_ATTCT Sarah Leigh Tag Q3_23_promote_green tag was added to STR: ATXN10_ATTCT.
Adult onset neurodegenerative disorder v4.28 TBP_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: TBP_CAG.
Adult onset neurodegenerative disorder v4.28 JPH3_CTG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: JPH3_CTG.
Adult onset neurodegenerative disorder v4.28 PPP2R2B_CAG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 PPP2R2B_CAG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 JPH3_CTG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 CSTB_CCCCGCCCCGCG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 CSTB_CCCCGCCCCGCG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 CACNA1A_CAG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 ATXN7_CAG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 ATXN3_CAG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 ATXN2_CAG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 ATXN1_CAG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 ATXN10_ATTCT Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 TBP_CAG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 JPH3_CTG Sarah Leigh changed review comment from: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; to: It is recommended this STR be promoted to Green following GMS review, as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 NOP56_GGCCTG Sarah Leigh reviewed STR: NOP56_GGCCTG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v4.28 PPP2R2B_CAG Sarah Leigh reviewed STR: PPP2R2B_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v4.28 JPH3_CTG Sarah Leigh commented on STR: JPH3_CTG: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.
Adult onset neurodegenerative disorder v4.28 CSTB_CCCCGCCCCGCG Sarah Leigh edited their review of STR: CSTB_CCCCGCCCCGCG: Added comment: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; Changed rating: GREEN
Adult onset neurodegenerative disorder v4.28 CACNA1A_CAG Sarah Leigh reviewed STR: CACNA1A_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v4.28 ATXN7_CAG Sarah Leigh reviewed STR: ATXN7_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v4.28 ATXN3_CAG Sarah Leigh reviewed STR: ATXN3_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v4.28 ATXN2_CAG Sarah Leigh reviewed STR: ATXN2_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v4.28 ATXN1_CAG Sarah Leigh reviewed STR: ATXN1_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v4.28 ATXN10_ATTCT Sarah Leigh reviewed STR: ATXN10_ATTCT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v4.28 TBP_CAG Sarah Leigh reviewed STR: TBP_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset neurodegenerative disorder v4.28 JPH3_CTG Sarah Leigh edited their review of STR: JPH3_CTG: Added comment: It is recommended this STR be promoted to Green following GMS review as the testing method for this clinicial indication is now WGS.; Changed rating: GREEN
Adult onset neurodegenerative disorder v4.28 ATN1_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: ATN1_CAG.
Adult onset neurodegenerative disorder v4.28 ATN1_CAG Sarah Leigh reviewed STR: ATN1_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Cystinosis v0.1 CTNS Achchuthan Shanmugasundram gene: CTNS was added
gene: CTNS was added to Cystinosis. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CTNS was set to BIALLELIC, autosomal or pseudoautosomal
Cystic fibrosis diagnostic test v0.1 CFTR Achchuthan Shanmugasundram gene: CFTR was added
gene: CFTR was added to Cystic fibrosis diagnostic test. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CFTR was set to BIALLELIC, autosomal or pseudoautosomal
Congenital adrenal hyperplasia diagnostic test v0.1 CYP21A2 Achchuthan Shanmugasundram gene: CYP21A2 was added
gene: CYP21A2 was added to Congenital adrenal hyperplasia diagnostic test. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CYP21A2 was set to BIALLELIC, autosomal or pseudoautosomal
Combined vitamin K-dependent clotting factor deficiency v0.1 VKORC1 Achchuthan Shanmugasundram gene: VKORC1 was added
gene: VKORC1 was added to Combined vitamin K-dependent clotting factor deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: VKORC1 was set to BIALLELIC, autosomal or pseudoautosomal
Combined vitamin K-dependent clotting factor deficiency v0.1 GGCX Achchuthan Shanmugasundram gene: GGCX was added
gene: GGCX was added to Combined vitamin K-dependent clotting factor deficiency. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: GGCX was set to BIALLELIC, autosomal or pseudoautosomal
Central congenital hypoventilation v0.1 PHOX2B Achchuthan Shanmugasundram gene: PHOX2B was added
gene: PHOX2B was added to Central congenital hypoventilation. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PHOX2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Carney complex v0.1 PRKAR1A Achchuthan Shanmugasundram gene: PRKAR1A was added
gene: PRKAR1A was added to Carney complex. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: PRKAR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Calcium-sensing receptor phenotypes v0.1 CASR Achchuthan Shanmugasundram gene: CASR was added
gene: CASR was added to Calcium-sensing receptor phenotypes. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CASR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
CADASIL v0.1 NOTCH3 Achchuthan Shanmugasundram gene: NOTCH3 was added
gene: NOTCH3 was added to CADASIL. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Blepharophimosis ptosis and epicanthus inversus v0.1 FOXL2 Achchuthan Shanmugasundram gene: FOXL2 was added
gene: FOXL2 was added to Blepharophimosis ptosis and epicanthus inversus. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: FOXL2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Beckwith-Wiedemann syndrome v0.1 CDKN1C Achchuthan Shanmugasundram gene: CDKN1C was added
gene: CDKN1C was added to Beckwith-Wiedemann syndrome. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: CDKN1C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Barth syndrome v0.1 TAZ Achchuthan Shanmugasundram gene: TAZ was added
gene: TAZ was added to Barth syndrome. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TAZ was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
BAP1 associated tumour predisposition syndrome v0.2 BAP1 Achchuthan Shanmugasundram gene: BAP1 was added
gene: BAP1 was added to BAP1 associated tumour predisposition syndrome. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Autoimmune Polyendocrine Syndrome v0.2 AIRE Achchuthan Shanmugasundram gene: AIRE was added
gene: AIRE was added to Autoimmune Polyendocrine Syndrome. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: AIRE was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Agammaglobulinaemia with absent BTK expression v0.7 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease
Acute intermittent porphyria v0.8 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease
Autoimmune lymphoproliferative syndrome with defective apoptosis v0.6 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease
Ataxia telangiectasia - mutation testing v0.7 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease
APC associated Polyposis v0.8 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease
Alveolar capillary dysplasia with misalignment of pulmonary veins v0.6 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease
Alstrom syndrome v0.6 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.7 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease
Wiskott-Aldrich syndrome v0.0 Achchuthan Shanmugasundram Added Panel Wiskott-Aldrich syndrome
Set list of related panels to R20
Set panel types to: GMS Rare Disease
Wilson disease v0.0 Achchuthan Shanmugasundram Added Panel Wilson disease
Set list of related panels to R172
Set panel types to: GMS Rare Disease
von Willebrand disease v0.0 Achchuthan Shanmugasundram Added Panel von Willebrand disease
Set list of related panels to R121
Set panel types to: GMS Rare Disease
Von Hippel Lindau syndrome v0.0 Achchuthan Shanmugasundram Added Panel Von Hippel Lindau syndrome
Set list of related panels to R225
Set panel types to: GMS Rare Disease
Variegate porphyria v0.0 Achchuthan Shanmugasundram Added Panel Variegate porphyria
Set list of related panels to R170
Set panel types to: GMS Rare Disease
Tuberous sclerosis v0.0 Achchuthan Shanmugasundram Added Panel Tuberous sclerosis
Set list of related panels to R228
Set panel types to: GMS Rare Disease
Thiamine metabolism dysfunction syndrome 2 v0.0 Achchuthan Shanmugasundram Added Panel Thiamine metabolism dysfunction syndrome 2
Set list of related panels to R395
Set panel types to: GMS Rare Disease
Thanatophoric dysplasia v0.0 Achchuthan Shanmugasundram Added Panel Thanatophoric dysplasia
Set list of related panels to R25
Set panel types to: GMS Rare Disease
Sickle cell, thalassaemia and other haemoglobinopathies v0.0 Achchuthan Shanmugasundram Added Panel Thalassaemia and other haemoglobinopathies
Set list of related panels to R93
Set panel types to: GMS Rare Disease
Tay-Sachs disease v0.0 Achchuthan Shanmugasundram Added Panel Tay-Sachs disease
Set list of related panels to R286
Set panel types to: GMS Rare Disease
Syndromic and non syndromic craniosynostosis involving midline sutures v0.0 Achchuthan Shanmugasundram Added Panel Syndromic and non syndromic craniosynostosis involving midline sutures
Set list of related panels to R416
Set panel types to: GMS Rare Disease
Subcutaneous panniculitis T-cell lymphoma (SPTCL) v0.0 Achchuthan Shanmugasundram Added Panel Subcutaneous panniculitis T-cell lymphoma (SPTCL)
Set list of related panels to R424
Set panel types to: GMS Rare Disease
Spinal muscular atrophy type 1 rare mutation testing v0.0 Achchuthan Shanmugasundram Added Panel Spinal muscular atrophy type 1 rare mutation testing
Set list of related panels to R71
Set panel types to: GMS Rare Disease
Smith-Lemli-Opitz syndrome v0.0 Achchuthan Shanmugasundram Added Panel Smith-Lemli-Opitz syndrome
Set list of related panels to R270
Set panel types to: GMS Rare Disease
Sitosterolaemia v0.0 Achchuthan Shanmugasundram Added Panel Sitosterolaemia
Set list of related panels to R323
Set panel types to: GMS Rare Disease
Short stature - SHOX deficiency v0.0 Achchuthan Shanmugasundram Added Panel Short stature - SHOX deficiency
Set list of related panels to R52
Set panel types to: GMS Rare Disease
Severe combined immunodeficiency with PNP deficiency v0.0 Achchuthan Shanmugasundram Added Panel Severe combined immunodeficiency with PNP deficiency
Set list of related panels to R234
Set panel types to: GMS Rare Disease
Severe combined immunodeficiency with adenosine deaminase deficiency v0.0 Achchuthan Shanmugasundram Added Panel Severe combined immunodeficiency with adenosine deaminase deficiency
Set list of related panels to R16
Set panel types to: GMS Rare Disease
Segmental or atypical neurofibromatosis type 1 testing v0.0 Achchuthan Shanmugasundram Added Panel Segmental or atypical neurofibromatosis type 1 testing
Set list of related panels to R376
Set panel types to: GMS Rare Disease
SCID with features of gamma chain deficiency v0.0 Achchuthan Shanmugasundram Added Panel SCID with features of gamma chain deficiency
Set list of related panels to R235
Set panel types to: GMS Rare Disease
Sandhoff disease v0.0 Achchuthan Shanmugasundram Added Panel Sandhoff disease
Set list of related panels to R285
Set panel types to: GMS Rare Disease
Retinoblastoma v0.0 Achchuthan Shanmugasundram Added Panel Retinoblastoma
Set list of related panels to R219
Set panel types to: GMS Rare Disease
Pulmonary alveolar microlithiasis v0.0 Achchuthan Shanmugasundram Added Panel Pulmonary alveolar microlithiasis
Set list of related panels to R426
Set panel types to: GMS Rare Disease
PTEN Hamartoma Tumour Syndrome v0.0 Achchuthan Shanmugasundram Added Panel PTEN Hamartoma Tumor Syndrome
Set list of related panels to R213
Set panel types to: GMS Rare Disease
Pseudoxanthoma elasticum v0.0 Achchuthan Shanmugasundram Added Panel Pseudoxanthoma elasticum
Set list of related panels to R420
Set panel types to: GMS Rare Disease
Primary hyperaldosteronism - KCNJ5 v0.0 Achchuthan Shanmugasundram Added Panel Primary hyperaldosteronism - KCNJ5
Set list of related panels to R344
Set panel types to: GMS Rare Disease
POLG-related disorder v0.0 Achchuthan Shanmugasundram Added Panel POLG-related disorder
Set list of related panels to R315
Set panel types to: GMS Rare Disease
Phenylketonuria v0.0 Achchuthan Shanmugasundram Added Panel Phenylketonuria
Set list of related panels to R283
Set panel types to: GMS Rare Disease
Peutz Jeghers Syndrome v0.0 Achchuthan Shanmugasundram Added Panel Peutz Jeghers Syndrome
Set list of related panels to R212
Set panel types to: GMS Rare Disease
Nijmegen breakage syndrome v0.0 Achchuthan Shanmugasundram Added Panel Nijmegen breakage syndrome
Set list of related panels to R259.2
Set panel types to: GMS Rare Disease
Niemann-Pick disease type A or B v0.0 Achchuthan Shanmugasundram Added Panel Niemann-Pick disease type A or B
Set list of related panels to R282
Set panel types to: GMS Rare Disease
Niemann Pick disease type C v0.0 Achchuthan Shanmugasundram Added Panel Niemann Pick disease type C
Set list of related panels to R380
Set panel types to: GMS Rare Disease
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v0.0 Achchuthan Shanmugasundram Added Panel Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome
Set list of related panels to R214
Set panel types to: GMS Rare Disease
Neutropaenia consistent with ELANE mutations v0.0 Achchuthan Shanmugasundram Added Panel Neutropaenia consistent with ELANE mutations
Set list of related panels to R313
Set panel types to: GMS Rare Disease
Neuronal ceroid lipofuscinosis type 2 v0.0 Achchuthan Shanmugasundram Added Panel Neuronal ceroid lipofuscinosis type 2
Set list of related panels to R271
Set panel types to: GMS Rare Disease
Neurofibromatosis type 1 (GMS) v0.0 Achchuthan Shanmugasundram Added Panel Neurofibromatosis type 1 (GMS)
Set list of related panels to R222
Set panel types to: GMS Rare Disease
Neonatal diabetes - small panel v0.0 Achchuthan Shanmugasundram Added Panel Neonatal diabetes - small panel
Set list of related panels to R143
Set panel types to: GMS Rare Disease
NARP syndrome or maternally inherited Leigh syndrome v0.0 Achchuthan Shanmugasundram Added Panel NARP syndrome or maternally inherited Leigh syndrome
Set list of related panels to R351
Set panel types to: GMS Rare Disease
Multiple exostoses v0.0 Achchuthan Shanmugasundram Added Panel Multiple exostoses
Set list of related panels to R390
Set panel types to: GMS Rare Disease
Multiple endocrine neoplasia type 2 v0.0 Achchuthan Shanmugasundram Added Panel Multiple endocrine neoplasia type 2
Set list of related panels to R218
Set panel types to: GMS Rare Disease
Mucopolysaccharidosis type VI v0.0 Achchuthan Shanmugasundram Added Panel Mucopolysaccharidosis type VI
Set list of related panels to R290
Set panel types to: GMS Rare Disease
Mucopolysaccharidosis type IVA v0.0 Achchuthan Shanmugasundram Added Panel Mucopolysaccharidosis type IVA
Set list of related panels to R287
Set panel types to: GMS Rare Disease
Mucopolysaccharidosis type IIIB v0.0 Achchuthan Shanmugasundram Added Panel Mucopolysaccharidosis type IIIB
Set list of related panels to R292
Set panel types to: GMS Rare Disease
Mucopolysaccharidosis type IIIA v0.0 Achchuthan Shanmugasundram Added Panel Mucopolysaccharidosis type IIIA
Set list of related panels to R291
Set panel types to: GMS Rare Disease
Mucopolysaccharidosis type II v0.0 Achchuthan Shanmugasundram Added Panel Mucopolysaccharidosis type II
Set list of related panels to R278
Set panel types to: GMS Rare Disease
Mucopolysaccharidosis type IH or S v0.0 Achchuthan Shanmugasundram Added Panel Mucopolysaccharidosis type IH/S
Set list of related panels to R277
Set panel types to: GMS Rare Disease
Mucolipidosis II and III Alpha or Beta v0.0 Achchuthan Shanmugasundram Added Panel Mucolipidosis II and III Alpha/Beta
Set list of related panels to R289
Set panel types to: GMS Rare Disease
Monitoring for G(M)CSF escape mutations v0.0 Achchuthan Shanmugasundram Added Panel Monitoring for G(M)CSF escape mutations
Set list of related panels to R338
Set panel types to: GMS Rare Disease
Mitochondrial neurogastrointestinal encephalopathy v0.0 Achchuthan Shanmugasundram Added Panel Mitochondrial neurogastrointestinal encephalopathy
Set list of related panels to R394
Set panel types to: GMS Rare Disease
Mitochondrial Complex V deficiency, TMEM70 type v0.0 Achchuthan Shanmugasundram Added Panel Mitochondrial Complex V deficiency, TMEM70 type
Set list of related panels to R396
Set panel types to: GMS Rare Disease
Lysosomal acid lipase deficiency v0.0 Achchuthan Shanmugasundram Added Panel Lysosomal acid lipase deficiency
Set list of related panels to R325
Set panel types to: GMS Rare Disease
Lymphoproliferative syndrome with absent SAP expression v0.0 Achchuthan Shanmugasundram Added Panel Lymphoproliferative syndrome with absent SAP expression
Set list of related panels to R17
Set panel types to: GMS Rare Disease
Krabbe disease - Saposin A deficiency v0.0 Achchuthan Shanmugasundram Added Panel Krabbe disease - Saposin A deficiency
Set list of related panels to R281
Set panel types to: GMS Rare Disease
Krabbe disease - GALC deficiency v0.0 Achchuthan Shanmugasundram Added Panel Krabbe disease - GALC deficiency
Set list of related panels to R280
Set panel types to: GMS Rare Disease
IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v0.0 Achchuthan Shanmugasundram Added Panel IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked
Set list of related panels to R157
Set panel types to: GMS Rare Disease
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v0.0 Achchuthan Shanmugasundram Added Panel Inherited susceptibility to acute lymphoblastoid leukaemia (ALL)
Set list of related panels to R366
Set panel types to: GMS Rare Disease
Inherited parathyroid cancer v0.0 Achchuthan Shanmugasundram Added Panel Inherited parathyroid cancer
Set list of related panels to R226
Set panel types to: GMS Rare Disease
Incontinentia pigmenti v0.0 Achchuthan Shanmugasundram Added Panel Incontinentia pigmenti
Set list of related panels to R239
Set panel types to: GMS Rare Disease
Hereditary angioedema types I and II v0.0 Achchuthan Shanmugasundram Added Panel Hereditary angioedema types I and II
Set list of related panels to R341
Set panel types to: GMS Rare Disease
Haemophagocytic syndrome with absent XIAP expression v0.0 Achchuthan Shanmugasundram Added Panel Haemophagocytic syndrome with absent XIAP expression
Set list of related panels to R18
Set panel types to: GMS Rare Disease
Haemophagocytic syndrome with absent perforin expression v0.0 Achchuthan Shanmugasundram Added Panel Haemophagocytic syndrome with absent perforin expression
Set list of related panels to R232
Set panel types to: GMS Rare Disease
Sickle cell, thalassaemia and other haemoglobinopathies trait or carrier testing v0.0 Achchuthan Shanmugasundram Added Panel Haemoglobinopathy trait or carrier testing
Set list of related panels to R361
Set panel types to: GMS Rare Disease
GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v0.0 Achchuthan Shanmugasundram Added Panel GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB
Set list of related panels to R288
Set panel types to: GMS Rare Disease
Glycogen storage disease V v0.0 Achchuthan Shanmugasundram Added Panel Glycogen storage disease V
Set list of related panels to R273
Set panel types to: GMS Rare Disease
Glucokinase-related fasting hyperglycaemia v0.0 Achchuthan Shanmugasundram Added Panel Glucokinase-related fasting hyperglycaemia
Set list of related panels to R142
Set panel types to: GMS Rare Disease
Generalised arterial calcification in infancy v0.0 Achchuthan Shanmugasundram Added Panel Generalised arterial calcification in infancy
Set list of related panels to R384
Set panel types to: GMS Rare Disease
Gaucher disease v0.0 Achchuthan Shanmugasundram Added Panel Gaucher disease
Set list of related panels to R272
Set panel types to: GMS Rare Disease
Fumarate hydratase-related tumour syndromes v0.0 Achchuthan Shanmugasundram Added Panel Fumarate hydratase-related tumour syndromes
Set list of related panels to R365
Set panel types to: GMS Rare Disease
Familial tumours of the nervous system v0.0 Achchuthan Shanmugasundram Added Panel Familial tumours of the nervous system
Set list of related panels to R221
Set panel types to: GMS Rare Disease
Familial dysalbuminaemic hyperthyroxinaemia v0.0 Achchuthan Shanmugasundram Added Panel Familial dysalbuminaemic hyperthyroxinaemia
Set list of related panels to R329
Set panel types to: GMS Rare Disease
Factor XIII deficiency v0.0 Achchuthan Shanmugasundram Added Panel Factor XIII deficiency
Set list of related panels to R122
Set panel types to: GMS Rare Disease
Factor XI deficiency v0.0 Achchuthan Shanmugasundram Added Panel Factor XI deficiency
Set list of related panels to R120
Set panel types to: GMS Rare Disease
Factor X deficiency v0.0 Achchuthan Shanmugasundram Added Panel Factor X deficiency
Set list of related panels to R119
Set panel types to: GMS Rare Disease
Factor VIII deficiency v0.0 Achchuthan Shanmugasundram Added Panel Factor VIII deficiency
Set list of related panels to R117
Set panel types to: GMS Rare Disease
Factor VII deficiency v0.0 Achchuthan Shanmugasundram Added Panel Factor VII deficiency
Set list of related panels to R116
Set panel types to: GMS Rare Disease
Factor V deficiency v0.0 Achchuthan Shanmugasundram Added Panel Factor V deficiency
Set list of related panels to R115
Set panel types to: GMS Rare Disease
Factor IX deficiency v0.0 Achchuthan Shanmugasundram Added Panel Factor IX deficiency
Set list of related panels to R118
Set panel types to: GMS Rare Disease
Factor II deficiency v0.0 Achchuthan Shanmugasundram Added Panel Factor II deficiency
Set list of related panels to R112
Set panel types to: GMS Rare Disease
Facioscapulohumeral muscular dystrophy - extended testing v0.0 Achchuthan Shanmugasundram Added Panel Facioscapulohumeral muscular dystrophy - extended testing
Set list of related panels to R345
Set panel types to: GMS Rare Disease
Fabry disease v0.0 Achchuthan Shanmugasundram Added Panel Fabry disease
Set list of related panels to R335
Set panel types to: GMS Rare Disease
Elastin-related phenotypes v0.0 Achchuthan Shanmugasundram Added Panel Elastin-related phenotypes
Set list of related panels to R140
Set panel types to: GMS Rare Disease
Duchenne or Becker muscular dystrophy v0.0 Achchuthan Shanmugasundram Added Panel Duchenne or Becker muscular dystrophy
Set list of related panels to R73
Set panel types to: GMS Rare Disease
DICER1-related cancer predisposition v0.0 Achchuthan Shanmugasundram Added Panel DICER1-related cancer predisposition
Set list of related panels to R364
Set panel types to: GMS Rare Disease
Cystinosis v0.0 Achchuthan Shanmugasundram Added Panel Cystinosis
Set list of related panels to R334
Set panel types to: GMS Rare Disease
Cystic fibrosis diagnostic test v0.0 Achchuthan Shanmugasundram Added Panel Cystic fibrosis diagnostic test
Set list of related panels to R184
Set panel types to: GMS Rare Disease
Congenital adrenal hyperplasia diagnostic test v0.0 Achchuthan Shanmugasundram Added Panel Congenital adrenal hyperplasia diagnostic test
Set list of related panels to R180
Set panel types to: GMS Rare Disease
Combined vitamin K-dependent clotting factor deficiency v0.0 Achchuthan Shanmugasundram Added Panel Combined vitamin K-dependent clotting factor deficiency
Set list of related panels to R123
Set panel types to: GMS Rare Disease
Central congenital hypoventilation v0.0 Achchuthan Shanmugasundram Added Panel Central congenital hypoventilation
Set list of related panels to R333
Set panel types to: GMS Rare Disease
Carney complex v0.0 Achchuthan Shanmugasundram Added Panel Carney complex
Set list of related panels to R156
Set panel types to: GMS Rare Disease
Calcium-sensing receptor phenotypes v0.0 Achchuthan Shanmugasundram Added Panel Calcium-sensing receptor phenotypes
Set list of related panels to R319
Set panel types to: GMS Rare Disease
CADASIL v0.0 Achchuthan Shanmugasundram Added Panel CADASIL
Set list of related panels to R337
Set panel types to: GMS Rare Disease
Blepharophimosis ptosis and epicanthus inversus v0.0 Achchuthan Shanmugasundram Added Panel Blepharophimosis ptosis and epicanthus inversus
Set list of related panels to R43
Set panel types to: GMS Rare Disease
Beckwith-Wiedemann syndrome v0.0 Achchuthan Shanmugasundram Added Panel Beckwith-Wiedemann syndrome
Set list of related panels to R49.3
Set panel types to: GMS Rare Disease
Barth syndrome v0.0 Achchuthan Shanmugasundram Added Panel Barth syndrome
Set list of related panels to R391
Set panel types to: GMS Rare Disease
BAP1 associated tumour predisposition syndrome v0.1 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease
Autoimmune Polyendocrine Syndrome v0.1 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease
Early onset or syndromic epilepsy v4.62 KDM6B Hannah Robinson gene: KDM6B was added
gene: KDM6B was added to Early onset or syndromic epilepsy. Sources: NHS GMS
Mode of inheritance for gene: KDM6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM6B were set to PMID: 37196654
Phenotypes for gene: KDM6B were set to Global developmental delay; Intellectual disability; Hypotonia; Joint hypermobility; seizures; Overgrowth
Penetrance for gene: KDM6B were set to Incomplete
Review for gene: KDM6B was set to GREEN
gene: KDM6B was marked as current diagnostic
Added comment: Information from Rots et al. 2023 (PMID:37196654): According to OMIM, heterozygous variants in KDM6B cause “neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities.” Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.).

In this cohort, 9/69 (13%) of individuals had seizures.

The majority of individuals had de novo variants but 9/85 individuals inherited the variant (five maternal, four paternal) from a mildly affected (developmental delay [DD], learning problems, autism spectrum disorder [ASD]) or clinically unaffected parent.
Sources: NHS GMS
Neuronal ceroid lipofuscinosis v2.2 CLCN6 Sarah Leigh edited their review of gene: CLCN6: Added comment: PMIDs: 16950870 & 21107136 report the characterization of CLCN6 deficient mouse model, which display some features of neuronal ceroid lipofuscinosis. PMID: 16950870 identifies two heterozygous CLCN6 variants (p.V580M, p.T628R) in 2/75 patients with late-onset neuronal ceroid lipofuscinosis, however, the authors concluded that there was insufficient evidence for these variants being responsible for the phenotype in the patients.; Changed rating: AMBER; Changed publications to: 21107136, 33217309, 16950870
Neuronal ceroid lipofuscinosis v2.2 CLCN6 Sarah Leigh Publications for gene: CLCN6 were set to 29667327; 26658788; 25794116; 21107136; 33217309
Clefting v4.78 UBE3B Achchuthan Shanmugasundram Classified gene: UBE3B as Amber List (moderate evidence)
Clefting v4.78 UBE3B Achchuthan Shanmugasundram Gene: ube3b has been classified as Amber List (Moderate Evidence).
Clefting v4.77 UBE3B Achchuthan Shanmugasundram gene: UBE3B was added
gene: UBE3B was added to Clefting. Sources: Literature
Mode of inheritance for gene: UBE3B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE3B were set to 23200864; 23687348; 37010288
Phenotypes for gene: UBE3B were set to Kaufman oculocerebrofacial syndrome, OMIM:244450
Review for gene: UBE3B was set to AMBER
Added comment: PMID:23687348 - One of two patients reported with biallelic variants in UBE3B in this study and one of four patients reported in PMID:23200864 and reviewed here had submucous cleft palate.

DECIPHER database - One of three patients with homozygous sequence variants in UBE3B had median cleft palate.
Sources: Literature
Clefting v4.76 TCF12 Achchuthan Shanmugasundram gene: TCF12 was added
gene: TCF12 was added to Clefting. Sources: Literature
Mode of inheritance for gene: TCF12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCF12 were set to 23354436; 31353793; 37010288
Phenotypes for gene: TCF12 were set to Craniosynostosis 3, OMIM:615314
Review for gene: TCF12 was set to RED
Added comment: Clefting has only been rarely reported in patients with TCF12 variants and hence this gene should be rated red.

PMID:23354436 - One of 73 individuals (from 38 families) reported with craniosynostosis and identified with heterozygous variants in TCF12 gene had cleft lip and cleft palate.

PMID:31353793 - Of two cases reported with heterozygous TCF12 variants, one had hidden cleft palate.

DECIPHER database - One of 11 patients with heterozygous sequence variants in TCF12 had bifid uvula.
Sources: Literature
Clefting v4.75 SOX11 Achchuthan Shanmugasundram gene: SOX11 was added
gene: SOX11 was added to Clefting. Sources: Literature
Mode of inheritance for gene: SOX11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOX11 were set to 29437512; 37010288
Phenotypes for gene: SOX11 were set to Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, OMIM:615866
Review for gene: SOX11 was set to RED
Added comment: Cleft palate is a minor clinical indication that is only observed in <10% of patients with SOX11 variants. Hence, this gene should be rated red.

PMID:29437512 - A 14-year-old boy with a phenotype resembling mild Coffin-Siris syndrome and identified with heterozygous SOX11 variant had cleft palate. However, cleft palate was not present in any of the previously reported patients (12 cases) reviewed in this publication.

DECIPHER database - Of 12 patients with heterozygous sequence variants in SOX11 gene, only one patient had cleft soft palate.
Sources: Literature
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Deleted their comment
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Deleted their comment
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Deleted their comment
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Classified gene: SMARCB1 as Amber List (moderate evidence)
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are 3 unrelated cases in total, these represent only a minor fraction of patients (from total of 23) reported with SMARCB1 variants. Hence, this gene should be rated amber.
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Gene: smarcb1 has been classified as Amber List (Moderate Evidence).
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Deleted their comment
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Classified gene: SMARCB1 as Amber List (moderate evidence)
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are 3 unrelated cases in total, these represent only a minor fraction of patients (from total of 23) reported with SMARCB1 variants. Hence, this gene should be rated amber.
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Gene: smarcb1 has been classified as Amber List (Moderate Evidence).
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Classified gene: SMARCB1 as Amber List (moderate evidence)
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are 3 unrelated cases in total, these represent only a minor fraction of patients (from total of 23) reported with SMARCB1 variants. Hence, this gene should be rated amber.
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Gene: smarcb1 has been classified as Amber List (Moderate Evidence).
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Classified gene: SMARCB1 as Amber List (moderate evidence)
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are 3 unrelated cases in total, these represent only a minor fraction of patients (from total of 23) reported with SMARCB1 variants. Hence, this gene should be rated amber.
Clefting v4.74 SMARCB1 Achchuthan Shanmugasundram Gene: smarcb1 has been classified as Amber List (Moderate Evidence).
Clefting v4.73 SMARCB1 Achchuthan Shanmugasundram Classified gene: SMARCB1 as Red List (low evidence)
Clefting v4.73 SMARCB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are 3 unrelated cases in total, these represent only a minor fraction of patients (from total of 23) reported with SMARCB1 variants. Hence, this gene should be rated amber.
Clefting v4.73 SMARCB1 Achchuthan Shanmugasundram Gene: smarcb1 has been classified as Red List (Low Evidence).
Clefting v4.72 SMARCB1 Achchuthan Shanmugasundram gene: SMARCB1 was added
gene: SMARCB1 was added to Clefting. Sources: Literature
Mode of inheritance for gene: SMARCB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCB1 were set to 25168959; 37010288
Phenotypes for gene: SMARCB1 were set to Coffin-Siris syndrome 3, OMIM:614608
Review for gene: SMARCB1 was set to AMBER
Added comment: PMID:25168959 - Two of ten patients reported with Coffin-Siris syndrome and heterozygous variants in SMARCB1 had cleft palate.

DECIPHER database - One of 13 patients identified with heterozygous sequence variants in SMARCB1 had cleft palate.
Sources: Literature
Clefting v4.71 SIN3A Achchuthan Shanmugasundram gene: SIN3A was added
gene: SIN3A was added to Clefting. Sources: Literature
Mode of inheritance for gene: SIN3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIN3A were set to 33437032; 37010288
Phenotypes for gene: SIN3A were set to Witteveen-Kolk syndrome, OMIM:613406
Review for gene: SIN3A was set to RED
Added comment: Clefting was reported only in a minor fraction of patients (<10%) and hence should be rated red.

PMID:33437032 - Of 28 patients with heterozugous variants in SIN3A gene, one patient had submucous cleft hard palate and another with deletion variant had orofacial cleft (both these are reported in DECIPHER database).

DECIPHER database - In addition to the above mentioned patients, one with heterozygous sequence variant had submucous cleft soft panel (from 31 in total), while an additional patient with deletion had cleft hard palate (from 54 patients with CNV variants).
Sources: Literature
Clefting v4.70 PUF60 Achchuthan Shanmugasundram changed review comment from: PMID:24140112 - One patient identified with heterozygous variant in PUF60 gene (p.His169Tyr) had cleft palate.

PMID:27804958 - Five patients were reported with sequence variants in PUF60 gene and none of them had cleft lip/ palate as one of the clinical presentations.

DECIPHER database - Of 27 patients with heterozygous sequence variants in PUF60, only one had submucous cleft hard palate.
Sources: Literature; to: Clefting has only been identified in a minor fraction of patients with monoallelic variants in PUF60 gene and hence this gene should be rated red in this panel.

PMID:24140112 - One patient identified with heterozygous variant in PUF60 gene (p.His169Tyr) had cleft palate.

PMID:27804958 - Five patients were reported with sequence variants in PUF60 gene and none of them had cleft lip/ palate as one of the clinical presentations.

DECIPHER database - Of 27 patients with heterozygous sequence variants in PUF60, only one had submucous cleft hard palate.
Sources: Literature
Clefting v4.70 PUF60 Achchuthan Shanmugasundram gene: PUF60 was added
gene: PUF60 was added to Clefting. Sources: Literature
Mode of inheritance for gene: PUF60 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PUF60 were set to 24140112; 27804958; 37010288
Phenotypes for gene: PUF60 were set to Verheij syndrome, OMIM:615583
Review for gene: PUF60 was set to RED
Added comment: PMID:24140112 - One patient identified with heterozygous variant in PUF60 gene (p.His169Tyr) had cleft palate.

PMID:27804958 - Five patients were reported with sequence variants in PUF60 gene and none of them had cleft lip/ palate as one of the clinical presentations.

DECIPHER database - Of 27 patients with heterozygous sequence variants in PUF60, only one had submucous cleft hard palate.
Sources: Literature
Clefting v4.69 POLR2A Achchuthan Shanmugasundram gene: POLR2A was added
gene: POLR2A was added to Clefting. Sources: Literature
Mode of inheritance for gene: POLR2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR2A were set to 31353023; 37010288
Phenotypes for gene: POLR2A were set to Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, OMIM:618603
Review for gene: POLR2A was set to RED
Added comment: This gene should be rated red as clefting has only been reported in a minor fraction of patients with monoallelic variants in POLR2A.

PMID:31353023 - 16 individuals were identified with heterozygous variants in POLR2A, of which only one patient had cleft lip.

DECIPHER database - Of 14 patients with heterozygous sequence variants, one had cleft palate and another had bifid uvula.
Sources: Literature
Clefting v4.68 POLA1 Achchuthan Shanmugasundram changed review comment from: PMID:3100651 - Nine patients from five unrelated families were identified with POLA1 variants, of which one patient from family C (has two reported patients) was reported with bifid uvula.

DECIPHER database - One of two patients with hemizygous sequence variants had bifid uvula.
Sources: Literature; to: Bifid uvula is a minor clinical indication that is only found in two patients with POLA1 variants and it is not fully penetrant in the family. Hence, this gene should be rated red.

PMID:3100651 - Nine patients from five unrelated families were identified with POLA1 variants, of which one patient from family C (has two reported patients) was reported with bifid uvula.

DECIPHER database - One of two patients with hemizygous sequence variants had bifid uvula.
Sources: Literature
Clefting v4.68 POLA1 Achchuthan Shanmugasundram gene: POLA1 was added
gene: POLA1 was added to Clefting. Sources: Literature
Mode of inheritance for gene: POLA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: POLA1 were set to 31006512; 37010288
Review for gene: POLA1 was set to RED
Added comment: PMID:3100651 - Nine patients from five unrelated families were identified with POLA1 variants, of which one patient from family C (has two reported patients) was reported with bifid uvula.

DECIPHER database - One of two patients with hemizygous sequence variants had bifid uvula.
Sources: Literature
Clefting v4.67 NOTCH2 Achchuthan Shanmugasundram Publications for gene: NOTCH2 were set to 9188663; 30329210; 37010288
Clefting v4.67 NOTCH2 Achchuthan Shanmugasundram Publications for gene: NOTCH2 were set to 9188663; 30329210
Clefting v4.66 NOTCH2 Achchuthan Shanmugasundram edited their review of gene: NOTCH2: Changed publications to: 9188663, 30329210, 37010288
Clefting v4.66 NOTCH2 Achchuthan Shanmugasundram Classified gene: NOTCH2 as Amber List (moderate evidence)
Clefting v4.66 NOTCH2 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are three cases reported with cleft lip/ palate or cleft of uvula, these are reported only in a minor proportion of patients and hence this gene can only be rated amber.
Clefting v4.66 NOTCH2 Achchuthan Shanmugasundram Gene: notch2 has been classified as Amber List (Moderate Evidence).
Clefting v4.65 NOTCH2 Achchuthan Shanmugasundram gene: NOTCH2 was added
gene: NOTCH2 was added to Clefting. Sources: Literature
Mode of inheritance for gene: NOTCH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH2 were set to 9188663; 30329210
Phenotypes for gene: NOTCH2 were set to Hajdu-Cheney syndrome, OMIM:102500
Review for gene: NOTCH2 was set to AMBER
Added comment: PMID:9188663 - An 8.5-year-old boy with NOTCH2 variant and Hajdu-Cheney syndrome was reported with cleft lip and palate.

PMID:30329210 - A 32-year-old male patient with a de novo truncating variant in NOTCH2 and presenting with Hajdu-Cheney syndrome had high arched palate and cleft of uvula.

DECIPHER database - One of seven patients with heterozygous sequence variants in NOTCH2 was identified with submucous cleft hard palate.
Sources: Literature
Intellectual disability v5.191 PSMC3 Dmitrijs Rots gene: PSMC3 was added
gene: PSMC3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC3 were set to PMID: 37256937
Phenotypes for gene: PSMC3 were set to neurodevelopmental delay
Mode of pathogenicity for gene: PSMC3 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: PSMC3 was set to GREEN
Added comment: 23 individuals with NDD due to 15 different de novo missense variants in PMID: 37256937.
Sources: Literature
Clefting v4.64 MAGEL2 Achchuthan Shanmugasundram gene: MAGEL2 was added
gene: MAGEL2 was added to Clefting. Sources: Literature
Mode of inheritance for gene: MAGEL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAGEL2 were set to 31397880; 37010288
Phenotypes for gene: MAGEL2 were set to Schaaf-Yang syndrome, OMIM:615547
Review for gene: MAGEL2 was set to RED
Added comment: Cleft palate is a minor feature of Schaaf-Yang syndrome and is present only in less than 10% of cases. Hence, this gene should be rated red.

PMID:31397880 - One of five patients presented in this study with heterozygous variants in MAGEL2 gene had cleft palate.

DECIPHER database - One of 20 patients with heterozygous sequence variants in MAGEL2 had cleft palate.
Sources: Literature
Clefting v4.63 EP300 Achchuthan Shanmugasundram changed review comment from: This gene should be rated red as clefting has only been reported in a very small fraction of patients (<5%) identified with monoallleic variants in EP300.

PMID:27648933 - One of 52 patients with Rubinstein-Taybi syndrome caused by monoallelic variants in EP300 gene had cleft lip and palate.

DECIPHER database - Of 58 patients with heterozygous sequence variants in EP300, cleft palate, orofacial cleft and bifid uvula were found in one patient each.
Sources: Literature; to: This gene should be rated red as clefting has only been reported in a very small fraction of patients (<5%) identified with monoallelic variants in EP300.

PMID:27648933 - One of 52 patients with Rubinstein-Taybi syndrome caused by monoallelic variants in EP300 gene had cleft lip and palate.

DECIPHER database - Of 58 patients with heterozygous sequence variants in EP300, cleft palate, orofacial cleft and bifid uvula were found in one patient each.
Sources: Literature
Clefting v4.63 EP300 Achchuthan Shanmugasundram gene: EP300 was added
gene: EP300 was added to Clefting. Sources: Literature
Mode of inheritance for gene: EP300 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EP300 were set to 27648933; 37010288
Phenotypes for gene: EP300 were set to Rubinstein-Taybi syndrome 2, OMIM:613684
Review for gene: EP300 was set to RED
Added comment: This gene should be rated red as clefting has only been reported in a very small fraction of patients (<5%) identified with monoallleic variants in EP300.

PMID:27648933 - One of 52 patients with Rubinstein-Taybi syndrome caused by monoallelic variants in EP300 gene had cleft lip and palate.

DECIPHER database - Of 58 patients with heterozygous sequence variants in EP300, cleft palate, orofacial cleft and bifid uvula were found in one patient each.
Sources: Literature
Clefting v4.62 CHD3 Achchuthan Shanmugasundram changed review comment from: Of 28 patients with heterozygous sequence variants in CHD3 gene from DECIPHER database, one patient had cleft palate and another had submucous cleft hard palate.
Sources: Literature; to: Of 28 patients with heterozygous sequence variants in CHD3 gene from DECIPHER database, one patient had cleft palate and another had submucous cleft hard palate.
Sources: Literature
Clefting v4.62 CHD3 Achchuthan Shanmugasundram gene: CHD3 was added
gene: CHD3 was added to Clefting. Sources: Literature
Mode of inheritance for gene: CHD3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD3 were set to 37010288
Phenotypes for gene: CHD3 were set to Snijders Blok-Campeau syndrome, OMIM:618205
Review for gene: CHD3 was set to RED
Added comment: Of 28 patients with heterozygous sequence variants in CHD3 gene from DECIPHER database, one patient had cleft palate and another had submucous cleft hard palate.
Sources: Literature
Clefting v4.61 AUTS2 Achchuthan Shanmugasundram Classified gene: AUTS2 as Amber List (moderate evidence)
Clefting v4.61 AUTS2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five cases reported with cleft lip/ palate. However, clefting has only been reported in less than 10% of patients with monoalellic variants in AUTS2 from the DECIPHER database. Hence, this gene should be rated amber.
Clefting v4.61 AUTS2 Achchuthan Shanmugasundram Gene: auts2 has been classified as Amber List (Moderate Evidence).
Clefting v4.60 AUTS2 Achchuthan Shanmugasundram gene: AUTS2 was added
gene: AUTS2 was added to Clefting. Sources: Literature
Mode of inheritance for gene: AUTS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AUTS2 were set to 31788251; 37010288
Phenotypes for gene: AUTS2 were set to Intellectual developmental disorder, autosomal dominant 26, OMIM:615834
Review for gene: AUTS2 was set to AMBER
Added comment: PMID:31788251 - A patient identified with a de novo heterozygous AUTS2 variant (c.1464_1467del ACTC/ p.Tyr488Ter) was reported with autism and cleft lip and palate.

DECIPHER database - Of 44 patients reported with heterozygous sequence variants, 4 patients had cleft lip or cleft palate (2 - cleft palate; 1 - cleft soft palate; 1 - unilateral cleft lip).
Sources: Literature
Clefting v4.59 ARID1A Achchuthan Shanmugasundram Phenotypes for gene: ARID1A were changed from to Coffin-Siris syndrome 2, OMIM:614607
Clefting v4.58 ARID1A Achchuthan Shanmugasundram edited their review of gene: ARID1A: Changed phenotypes to: Coffin-Siris syndrome 2, OMIM:614607
Clefting v4.58 ARID1A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Clefting is a minor feature on patients with monoallelic variants in ARID1A gene and it can be rated amber although there are three cases with clefting form a total of 34 cases.; to: Comment on list classification: Clefting is a minor feature on patients with monoallelic variants in ARID1A gene and it should be rated amber although there are three cases with clefting (from a total of 34 cases).
Clefting v4.58 ARID1A Achchuthan Shanmugasundram Classified gene: ARID1A as Amber List (moderate evidence)
Clefting v4.58 ARID1A Achchuthan Shanmugasundram Added comment: Comment on list classification: Clefting is a minor feature on patients with monoallelic variants in ARID1A gene and it can be rated amber although there are three cases with clefting form a total of 34 cases.
Clefting v4.58 ARID1A Achchuthan Shanmugasundram Gene: arid1a has been classified as Amber List (Moderate Evidence).
Clefting v4.57 ARID1A Achchuthan Shanmugasundram gene: ARID1A was added
gene: ARID1A was added to Clefting. Sources: Literature
Mode of inheritance for gene: ARID1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARID1A were set to 25168959; 37010288
Review for gene: ARID1A was set to AMBER
Added comment: PMID:25168959 - Two of eight patients with heterozygous variants in ARID1A gene had cleft palate.

DECIPHER database - One of 26 patients with heterozygous sequence variants in ARID1A gene had cleft palate.
Sources: Literature
Clefting v4.56 ADNP Achchuthan Shanmugasundram changed review comment from: PMID:29724491 - One child from a worldwide cohort of 78 individuals with variants in ADNP gene had submucous cleft palate.

DECIPHER database - Of 66 patients identified with heterozygous sequence variants in ADNP gene, one each (three in total) was reported with cleft soft palate, submucous cleft hard palate and submucous cleft lip.
Sources: Literature; to: Cleft lip/ palate has only been reported rarely in patients identified with monoallelic variants in ADNP gene.

PMID:29724491 - One child from a worldwide cohort of 78 individuals with variants in ADNP gene had submucous cleft palate.

DECIPHER database - Of 66 patients identified with heterozygous sequence variants in ADNP gene, one each (three in total) was reported with cleft soft palate, submucous cleft hard palate and submucous cleft lip.
Sources: Literature
Clefting v4.56 ADNP Achchuthan Shanmugasundram gene: ADNP was added
gene: ADNP was added to Clefting. Sources: Literature
Mode of inheritance for gene: ADNP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADNP were set to 29724491; 37010288
Phenotypes for gene: ADNP were set to Helsmoortel-van der Aa syndrome, OMIM:615873
Review for gene: ADNP was set to RED
Added comment: PMID:29724491 - One child from a worldwide cohort of 78 individuals with variants in ADNP gene had submucous cleft palate.

DECIPHER database - Of 66 patients identified with heterozygous sequence variants in ADNP gene, one each (three in total) was reported with cleft soft palate, submucous cleft hard palate and submucous cleft lip.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.22 OTULIN Boaz Palterer reviewed gene: OTULIN: Rating: ; Mode of pathogenicity: None; Publications: 35587511; Phenotypes: life-threatening staphylococcal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset dystonia, chorea or related movement disorder v3.17 DNAJC6 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: DNAJC6.
Childhood onset dystonia, chorea or related movement disorder v3.17 DNAJC6 Sarah Leigh Classified gene: DNAJC6 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.17 DNAJC6 Sarah Leigh Gene: dnajc6 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.22 ARPC5 Boaz Palterer gene: ARPC5 was added
gene: ARPC5 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ARPC5 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ARPC5 were set to immunodeficiency; autoimmunity; inflammation; dysmorphisms; impaired wound healing; scoliosis; pneumatoceles; anemia
Penetrance for gene: ARPC5 were set to unknown
Review for gene: ARPC5 was set to GREEN
Added comment: Nunes-Santos et al. described 2 unrelated patients from 2 kindreds woith germline biallelic null mutations in ARPC5 presenting with a complex actinopathy phenotype of increased susceptibility to infections, autoimmunity, inflammation, and dysmorphisms.
There is strong biological rationale: ARPC5 is part of the Arp2/3 complex, related to WAS in Wiskott-Aldrich syndrome and ARPC1B deficiency. Strong functional ex vivo and in vitro data is presented.
( https://doi.org/10.1038/s41467-023-39272-0 )
Sources: Literature
Early onset or syndromic epilepsy v4.62 DNAJC6 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: DNAJC6.
Early onset or syndromic epilepsy v4.62 DNAJC6 Sarah Leigh Classified gene: DNAJC6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.62 DNAJC6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v4.62 DNAJC6 Sarah Leigh Gene: dnajc6 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.16 DNAJC6 Sarah Leigh Classified gene: DNAJC6 as Green List (high evidence)
Childhood onset dystonia, chorea or related movement disorder v3.16 DNAJC6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset dystonia, chorea or related movement disorder v3.16 DNAJC6 Sarah Leigh Gene: dnajc6 has been classified as Green List (High Evidence).
Adult onset dystonia, chorea or related movement disorder v3.4 DNAJC6 Sarah Leigh Publications for gene: DNAJC6 were set to 26528954; 23211418; 27687717; 26703368; 22563501
Adult onset neurodegenerative disorder v4.28 DNAJC6 Sarah Leigh Publications for gene: DNAJC6 were set to 23211418; 27687717; 26528954; 22563501; 26703368
Parkinson Disease and Complex Parkinsonism v1.116 DNAJC6 Sarah Leigh Publications for gene: DNAJC6 were set to 26528954; 27687717; 26703368; 22563501; 23211418
Childhood onset dystonia, chorea or related movement disorder v3.15 DNAJC6 Sarah Leigh Publications for gene: DNAJC6 were set to 34175496
Childhood onset dystonia, chorea or related movement disorder v3.14 DNAJC6 Sarah Leigh Phenotypes for gene: DNAJC6 were changed from to Parkinson disease 19b, early-onset, OMIM:615528; Parkinson disease 19a juvenile-onset, OMIM:615528; juvenile onset Parkinson disease 19A, MONDO:0014231
Childhood onset dystonia, chorea or related movement disorder v3.13 DNAJC6 Sarah Leigh reviewed gene: DNAJC6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v4.61 DNAJC6 Sarah Leigh edited their review of gene: DNAJC6: Added comment: DNAJC6 variants are associated with Parkinson disease 19b, early-onset (OMIM:615528), but not with a phenotype in Gen2Phen. At least nine variants have been reported in unrelated families. Seizures were reported in 5/9 families and dystonia was reported in 4/9 families reported (data review in PMID: 34175496.; Changed rating: GREEN
Primary immunodeficiency or monogenic inflammatory bowel disease v4.22 DOCK11 Boaz Palterer gene: DOCK11 was added
gene: DOCK11 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: DOCK11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DOCK11 were set to 36952639
Phenotypes for gene: DOCK11 were set to early-onset autoimmunity; cytopenia; systemic lupus erythematosus; dermatitis; enteropathy
Penetrance for gene: DOCK11 were set to unknown
Review for gene: DOCK11 was set to GREEN
Added comment: Boussard et al. described 8 male patients, from 7 unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients presented with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Extensive ex vivo and in vitro functional validation.
Sources: Literature
Clefting v4.55 ZC4H2 Achchuthan Shanmugasundram changed review comment from: PMID:31206972 - Of 42 families identified with variants in de novo and inherited heterozygous variants in ZC4H2 gene, eight patients had cleft palate in addition to several other clinical presentations. These included one patient with cleft palate from the DDD study (DECIPHER database)

DECIPHER database - Of 13 patients with monoallelic sequence variants, three patients had cleft palate.

Cleft palate has been recorded as one of the clinical presentations of female-restricted Wieacker-Wolff syndrome (MIM #301041) in OMIM.
Sources: Literature; to: PMID:31206972 - Of 42 families identified with de novo and inherited variants in ZC4H2 gene, eight patients had cleft palate in addition to several other clinical presentations. These included one patient with cleft palate from the DDD study (DECIPHER database)

DECIPHER database - Of 13 patients with sequence variants, three patients had cleft palate.

Cleft palate has been recorded as one of the clinical presentations of female-restricted Wieacker-Wolff syndrome (MIM #301041) in OMIM.
Sources: Literature
Clefting v4.55 ZC4H2 Achchuthan Shanmugasundram Mode of inheritance for gene: ZC4H2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Clefting v4.54 ZC4H2 Achchuthan Shanmugasundram edited their review of gene: ZC4H2: 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)
Clefting v4.54 ZC4H2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are ten patients reported with cleft palate. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are ten unrelated patients reported with cleft palate. Hence, this gene can be promoted to green rating in the next GMS update.
Clefting v4.54 ZC4H2 Achchuthan Shanmugasundram changed review comment from: PMID:31206972 - Of 42 families identified with variants in de novo and inherited heterozygous variants in ZC4H2 gene, eight patients were had cleft palate in addition to several other clinical presentations. These included one patient with cleft palate from the DDD study (DECIPHER database)

DECIPHER database - Of 13 patients with monoallelic sequence variants, three patients had cleft palate.

Cleft palate has been recorded as one of the clinical presentations of female-restricted Wieacker-Wolff syndrome (MIM #301041) in OMIM.
Sources: Literature; to: PMID:31206972 - Of 42 families identified with variants in de novo and inherited heterozygous variants in ZC4H2 gene, eight patients had cleft palate in addition to several other clinical presentations. These included one patient with cleft palate from the DDD study (DECIPHER database)

DECIPHER database - Of 13 patients with monoallelic sequence variants, three patients had cleft palate.

Cleft palate has been recorded as one of the clinical presentations of female-restricted Wieacker-Wolff syndrome (MIM #301041) in OMIM.
Sources: Literature
Adult onset dystonia, chorea or related movement disorder v3.3 DNAJC6 Sarah Leigh Phenotypes for gene: DNAJC6 were changed from Parkinson disease 19, juvenile-onset, OMIM:615528; Parkinson disease 19b, early-onset, OMIM:615528 to Parkinson disease 19b, early-onset, OMIM:615528; Parkinson disease 19a juvenile-onset, OMIM:615528; juvenile onset Parkinson disease 19A, MONDO:0014231
Adult onset neurodegenerative disorder v4.27 DNAJC6 Sarah Leigh Phenotypes for gene: DNAJC6 were changed from Parkinson disease 19b, early-onset, OMIM:615528; Parkinson disease 19a, juvenile-onset, OMIM:615528 to Parkinson disease 19b, early-onset, OMIM:615528; Parkinson disease 19a juvenile-onset, OMIM:615528; juvenile onset Parkinson disease 19A, MONDO:0014231
Parkinson Disease and Complex Parkinsonism v1.115 DNAJC6 Sarah Leigh Phenotypes for gene: DNAJC6 were changed from Parkinson disease 19, juvenile-onset, 615528; Parkinson disease 19a, juvenile-onset; Parkinson disease 19b, early-onset to Parkinson disease 19b, early-onset, OMIM:615528; Parkinson disease 19a juvenile-onset, OMIM:615528; juvenile onset Parkinson disease 19A, MONDO:0014231
Early onset or syndromic epilepsy v4.61 DNAJC6 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v4.61 DNAJC6 Sarah Leigh Phenotypes for gene: DNAJC6 were changed from Parkinson disease 19b, early-onset, OMIM:615528; juvenile onset Parkinson disease 19A, MONDO:0014231 to Parkinson disease 19b, early-onset, OMIM:615528; Parkinson disease 19a juvenile-onset, OMIM:615528; juvenile onset Parkinson disease 19A, MONDO:0014231
Early onset or syndromic epilepsy v4.60 DNAJC6 Sarah Leigh Mode of inheritance for gene: DNAJC6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Clefting v4.54 ZC4H2 Achchuthan Shanmugasundram changed review comment from: PMID:31206972 - Of 42 families identified with variants in de novo and inherited heterozygous variants in ZC4H2 gene, eight patients were had cleft palate in addition to several other clinical presentations. These included one patient with cleft palate from the DDD study (DECIPHER database)

DECIPHER database - Of 13 patients with monoallelic sequence variants, three patients had cleft palate.
Sources: Literature; to: PMID:31206972 - Of 42 families identified with variants in de novo and inherited heterozygous variants in ZC4H2 gene, eight patients were had cleft palate in addition to several other clinical presentations. These included one patient with cleft palate from the DDD study (DECIPHER database)

DECIPHER database - Of 13 patients with monoallelic sequence variants, three patients had cleft palate.

Cleft palate has been recorded as one of the clinical presentations of female-restricted Wieacker-Wolff syndrome (MIM #301041) in OMIM.
Sources: Literature
Clefting v4.54 ZC4H2 Achchuthan Shanmugasundram Classified gene: ZC4H2 as Amber List (moderate evidence)
Clefting v4.54 ZC4H2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are ten patients reported with cleft palate. Hence, this gene can be promoted to green rating in the next GMS update.
Clefting v4.54 ZC4H2 Achchuthan Shanmugasundram Gene: zc4h2 has been classified as Amber List (Moderate Evidence).
Clefting v4.53 ZC4H2 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: ZC4H2.
Clefting v4.53 ZC4H2 Achchuthan Shanmugasundram gene: ZC4H2 was added
gene: ZC4H2 was added to Clefting. Sources: Literature
Mode of inheritance for gene: ZC4H2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZC4H2 were set to 31206972; 37010288
Phenotypes for gene: ZC4H2 were set to Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Review for gene: ZC4H2 was set to GREEN
Added comment: PMID:31206972 - Of 42 families identified with variants in de novo and inherited heterozygous variants in ZC4H2 gene, eight patients were had cleft palate in addition to several other clinical presentations. These included one patient with cleft palate from the DDD study (DECIPHER database)

DECIPHER database - Of 13 patients with monoallelic sequence variants, three patients had cleft palate.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.22 SRP72 Lauma Freimane gene: SRP72 was added
gene: SRP72 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature,Research
Mode of inheritance for gene: SRP72 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRP72 were set to 32098966
Phenotypes for gene: SRP72 were set to Familial MDS/AML; inherited bone marrow failure syndromes (IBMFS); congenital neutropenia; Shwachman-Diamond syndrome
Early onset or syndromic epilepsy v4.59 DNAJC6 Sarah Leigh Publications for gene: DNAJC6 were set to 22563501; 23211418; 26528954; 34175496; 26703368
Early onset or syndromic epilepsy v4.58 DNAJC6 Sarah Leigh Publications for gene: DNAJC6 were set to 23211418; 34175496
Early onset or syndromic epilepsy v4.57 DNAJC6 Sarah Leigh Publications for gene: DNAJC6 were set to
Early onset or syndromic epilepsy v4.56 DNAJC6 Sarah Leigh Added comment: Comment on phenotypes: OMIM:615528 also includes Parkinson disease 19a, juvenile-onset
Early onset or syndromic epilepsy v4.56 DNAJC6 Sarah Leigh Phenotypes for gene: DNAJC6 were changed from to Parkinson disease 19b, early-onset, OMIM:615528; juvenile onset Parkinson disease 19A, MONDO:0014231
Early onset or syndromic epilepsy v4.55 SAMD12 Sarah Leigh reviewed gene: SAMD12: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Clefting v4.52 TRRAP Achchuthan Shanmugasundram changed review comment from: PMID:30827496 - Out of 13 unrelated individuals with a complex syndromic neurodevelopmental disorder comprising global developmental delay and intellectual disability and identified with monoallelic variants in TRRAP gene, five had cleft lip and palate.

DECIPHER database - Out of 18 patients with heterozygous sequence variants in TRRAP gene, two were reported with cleft lip and palate.
Sources: Literature; to: PMID:30827496 - Out of 13 unrelated individuals with a complex syndromic neurodevelopmental disorder comprising global developmental delay and intellectual disability and identified with monoallelic variants in TRRAP gene, five had cleft lip and palate.

DECIPHER database - Out of 18 patients with heterozygous sequence variants in TRRAP gene, two were reported with cleft lip and palate.

OMIM has also recorded cleft lip and palate as clinical presentations of the syndrome associated with dominant variants in TRRAP (MIM #618454).
Sources: Literature
Clefting v4.52 TRRAP Achchuthan Shanmugasundram Deleted their comment
Clefting v4.52 TRRAP Achchuthan Shanmugasundram Classified gene: TRRAP as Amber List (moderate evidence)
Clefting v4.52 TRRAP Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (7 unrelated cases) for this gene to be promoted to green rating at the next major update.
Clefting v4.52 TRRAP Achchuthan Shanmugasundram Gene: trrap has been classified as Amber List (Moderate Evidence).
Clefting v4.52 TRRAP Achchuthan Shanmugasundram Classified gene: TRRAP as Amber List (moderate evidence)
Clefting v4.52 TRRAP Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (7 unrelated cases) for this gene to be promoted green rating at the next major update.
Clefting v4.52 TRRAP Achchuthan Shanmugasundram Gene: trrap has been classified as Amber List (Moderate Evidence).
Clefting v4.51 TRRAP Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: TRRAP.
Clefting v4.51 TRRAP Achchuthan Shanmugasundram gene: TRRAP was added
gene: TRRAP was added to Clefting. Sources: Literature
Mode of inheritance for gene: TRRAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRRAP were set to 30827496; 37010288
Phenotypes for gene: TRRAP were set to Developmental delay with or without dysmorphic facies and autism, OMIM:618454
Review for gene: TRRAP was set to GREEN
Added comment: PMID:30827496 - Out of 13 unrelated individuals with a complex syndromic neurodevelopmental disorder comprising global developmental delay and intellectual disability and identified with monoallelic variants in TRRAP gene, five had cleft lip and palate.

DECIPHER database - Out of 18 patients with heterozygous sequence variants in TRRAP gene, two were reported with cleft lip and palate.
Sources: Literature