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Skeletal dysplasia v2.165 LPIN2 Arina Puzriakova Phenotypes for gene: LPIN2 were changed from Majeed syndrome (Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia) 609628 to Majeed syndrome, OMIM:609628; Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia
Rare anaemia v1.32 LPIN2 Arina Puzriakova Phenotypes for gene: LPIN2 were changed from Majeed syndrome, 609628; Microcytic anemia; Congenital dyserythropoietic anemia; CDA; 609628 Majeed syndrome; Majeed syndrome; 609628 Microcytic anemia to Majeed syndrome, OMIM:609628; Microcytic anemia; Congenital dyserythropoietic anemia
Cytopenias and congenital anaemias v1.94 LPIN2 Arina Puzriakova Phenotypes for gene: LPIN2 were changed from Microcytic anemia; Congenital dyserythropoietic anemia; CDA; Majeed syndrome, 609628 to Majeed syndrome, OMIM:609628; Microcytic anemia; Congenital dyserythropoietic anemia
Primary immunodeficiency or monogenic inflammatory bowel disease v2.507 LPIN2 Arina Puzriakova Phenotypes for gene: LPIN2 were changed from Majeed syndrome 609628; Other autoinflammatory diseases with known genetic defect; Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders; Autoinflammatory Disorders to Majeed syndrome, OMIM:609628; Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders; Autoinflammatory Disorders
COVID-19 research v1.94 LPIN2 Arina Puzriakova Phenotypes for gene: LPIN2 were changed from Other autoinflammatory diseases with known genetic defect; Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders; Autoinflammatory Disorders; Majeed syndrome 609628 to Majeed syndrome, OMIM:609628; Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders; Autoinflammatory Disorders
Periodic fever syndromes v1.18 LPIN2 Arina Puzriakova Phenotypes for gene: LPIN2 were changed from Hereditary Periodic Fever Syndromes; Majeed syndrome, 609628 to Majeed syndrome, OMIM:609628
Generalised pustular psoriasis v1.10 IL36RN Arina Puzriakova Phenotypes for gene: IL36RN were changed from Psoriasis 14, pustular 614204 to Psoriasis 14, pustular, OMIM:614204
Primary immunodeficiency or monogenic inflammatory bowel disease v2.506 IL36RN Arina Puzriakova Phenotypes for gene: IL36RN were changed from Psoriasis 14, generalized pustular 614204; Other autoinflammatory diseases with known genetic defect; Pustular psoriasis; Autoinflammatory Disorders to Psoriasis 14, pustular, OMIM:614204; Autoinflammatory Disorders
Rare genetic inflammatory skin disorders v1.47 IL36RN Arina Puzriakova Phenotypes for gene: IL36RN were changed from PSORIASIS 14, PUSTULAR, OMIM:614204 to Psoriasis 14, pustular, OMIM:614204
COVID-19 research v1.93 IL36RN Arina Puzriakova Phenotypes for gene: IL36RN were changed from Other autoinflammatory diseases with known genetic defect; Psoriasis 14, generalized pustular 614204; Autoinflammatory Disorders; Pustular psoriasis to Psoriasis 14, pustular, OMIM:614204; Autoinflammatory Disorders
Periodic fever syndromes v1.17 IL36RN Arina Puzriakova Phenotypes for gene: IL36RN were changed from Psoriasis 14, pustular, 614204; DITRA; recurrent flares of pustular rash with fever to Psoriasis 14, pustular, OMIM:614204; Recurrent flares of pustular rash with fever
Rare genetic inflammatory skin disorders v1.46 IL1RN Arina Puzriakova Phenotypes for gene: IL1RN were changed from OSTEOMYELITIS, STERILE MULTIFOCAL, WITH PERIOSTITIS AND PUSTULOSIS, OMIM:612852 to Interleukin 1 receptor antagonist deficiency, OMIM:612852
COVID-19 research v1.92 IL1RN Arina Puzriakova Phenotypes for gene: IL1RN were changed from Other autoinflammatory diseases with known genetic defect; DIRA; Interleukin 1 receptor antagonist deficiency 612852; Autoinflammatory Disorders; sterile multifocal osteomyelitis, periostitis, and pustulosis; Neonatal onset of sterile multifocal osteomyelitis, periostitis and pustulosis. to Interleukin 1 receptor antagonist deficiency, OMIM:612852; Sterile multifocal osteomyelitis, periostitis, and pustulosis; DIRA; Autoinflammatory Disorders
Primary immunodeficiency or monogenic inflammatory bowel disease v2.505 IL1RN Arina Puzriakova Phenotypes for gene: IL1RN were changed from Interleukin 1 receptor antagonist deficiency 612852; sterile multifocal osteomyelitis, periostitis, and pustulosis; Other autoinflammatory diseases with known genetic defect; DIRA; Neonatal onset of sterile multifocal osteomyelitis, periostitis and pustulosis.; Autoinflammatory Disorders to Interleukin 1 receptor antagonist deficiency, OMIM:612852; Sterile multifocal osteomyelitis, periostitis, and pustulosis; DIRA; Autoinflammatory Disorders
Skeletal dysplasia v2.164 IL1RN Arina Puzriakova Phenotypes for gene: IL1RN were changed from Interleukin 1 receptor antagonist deficiency 612852; Interleukin 1 receptor antagonist deficiency 612852 to Interleukin 1 receptor antagonist deficiency, OMIM:612852
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.64 IL1RN Arina Puzriakova Phenotypes for gene: IL1RN were changed from {Gastric cancer risk after H. pylori infection}, 137215; {Microvascular complications of diabetes 4}, 612628; Interleukin 1 receptor antagonist deficiency, 612852; to {Microvascular complications of diabetes 4}, OMIM:612628
Periodic fever syndromes v1.16 IL1RN Arina Puzriakova Phenotypes for gene: IL1RN were changed from Interleukin 1 receptor antagonist deficiency, 612852; OMPP; DIRA syndrome; recurrent fever to Interleukin 1 receptor antagonist deficiency, OMIM:612852
Autoinflammatory disorders v0.0 Arina Puzriakova Added Panel Autoinflammatory disorders
Set panel types to: GMS Rare Disease
Early onset or syndromic epilepsy v2.483 SCN8A Helen Lord reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31625145; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 HNRNPK Helen Lord reviewed gene: HNRNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: 32588992; Phenotypes: Au Kline syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 LTBP1 Helen Lord reviewed gene: LTBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33991472; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 MASP1 Helen Lord reviewed gene: MASP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21258343, 7677137, 29168297; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 MASP1 Helen Lord Deleted their review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 MASP1 Helen Lord commented on gene: MASP1
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 ZNF462 Helen Lord reviewed gene: ZNF462: Rating: GREEN; Mode of pathogenicity: None; Publications: 28513610, 31361404; Phenotypes: Weiss Kruszka syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 CHD7 Helen Lord changed review comment from: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review; to: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 CHD7 Helen Lord changed review comment from: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review; to: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review
Intellectual disability v3.1485 MYO5B Arina Puzriakova Phenotypes for gene: MYO5B were changed from Microvillus inclusion disease, 251850 to Diarrhea 2, with microvillus atrophy, OMIM:251850
Fetal anomalies v1.823 MYO5B Arina Puzriakova Phenotypes for gene: MYO5B were changed from MICROVILLUS INCLUSION DISEASE to Diarrhea 2, with microvillus atrophy, OMIM:251850
Intestinal failure or congenital diarrhoea v1.44 MYO5B Arina Puzriakova Phenotypes for gene: MYO5B were changed from Microvillus inclusion disease, OMIM:251850 to Diarrhea 2, with microvillus atrophy, OMIM:251850
Cholestasis v1.99 MYO5B Arina Puzriakova Phenotypes for gene: MYO5B were changed from Microvillus inclusion disease, 251850; Cholestasis; MYO5B associated disease to Diarrhea 2, with microvillus atrophy, OMIM:251850
COVID-19 research v1.91 MYO5B Arina Puzriakova Phenotypes for gene: MYO5B were changed from Microvillus inclusion disease 251850 to Diarrhea 2, with microvillus atrophy, OMIM:251850
Neonatal cholestasis v1.22 MYO5B Arina Puzriakova Phenotypes for gene: MYO5B were changed from MYO5B associated disease; Cholestasis to Diarrhea 2, with microvillus atrophy, OMIM:251850
Gastrointestinal epithelial barrier disorders v1.63 MYO5B Arina Puzriakova Phenotypes for gene: MYO5B were changed from Microvillus inclusion disease 251850; Microvillus inclusion disease to Diarrhea 2, with microvillus atrophy, OMIM:251850
Primary immunodeficiency or monogenic inflammatory bowel disease v2.504 MYO5B Arina Puzriakova Phenotypes for gene: MYO5B were changed from Microvillus inclusion disease 251850 to Diarrhea 2, with microvillus atrophy, OMIM:251850
Retinal disorders v2.241 PAK2 Arina Puzriakova gene: PAK2 was added
gene: PAK2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: PAK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PAK2 were set to 33693784
Phenotypes for gene: PAK2 were set to Knobloch 2 syndrome
Review for gene: PAK2 was set to RED
Added comment: Antonarakis et al., 2021 (PMID: 33693784) reported two affected siblings from a non-consanguineous New Zealand family. Both had retinal detachment and interstitial parenchymal pulmonary changes on chest X-rays, but only one child had additional significant features such as cataract, posterior encephalocele, severe DD/ID with ASD, and epilepsy. WES revealed a heterozygous PAK2 variant (c.1303 G>A, p.Glu435Lys) in both individuals that apparently occurred de novo indicating parental germ-line mosaicism; however, mosaicism could not be detected by deep sequencing of blood parental DNA. Functional studies showed that the variant, located in the kinase domain, results in a partial loss of the kinase activity.
Sources: Literature
Likely inborn error of metabolism v2.213 PDK3 Arina Puzriakova Publications for gene: PDK3 were set to 27604308; 26801680; 28902413; 23297365
Mitochondrial disorders v2.80 PDK3 Arina Puzriakova Publications for gene: PDK3 were set to
Possible mitochondrial disorder - nuclear genes v1.63 PDK3 Arina Puzriakova Publications for gene: PDK3 were set to
Possible mitochondrial disorder - nuclear genes v1.62 PDK3 Arina Puzriakova reviewed gene: PDK3: Rating: ; Mode of pathogenicity: None; Publications: 23297365, 26801680, 27388934, 28902413, 32504000, 34387338; Phenotypes: Charcot-Marie-Tooth disease, X-linked dominant, 6, OMIM:300905; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mitochondrial disorders v2.79 PDK3 Arina Puzriakova reviewed gene: PDK3: Rating: ; Mode of pathogenicity: None; Publications: 23297365, 26801680, 27388934, 28902413, 32504000, 34387338; Phenotypes: Charcot-Marie-Tooth disease, X-linked dominant, 6, OMIM:300905; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mitochondrial disorders v2.79 PDK3 Arina Puzriakova Tag Q1_22_phenotype tag was added to gene: PDK3.
Possible mitochondrial disorder - nuclear genes v1.62 PDK3 Arina Puzriakova Tag Q1_22_phenotype tag was added to gene: PDK3.
Likely inborn error of metabolism v2.212 PDK3 Arina Puzriakova Tag Q1_22_phenotype tag was added to gene: PDK3.
Likely inborn error of metabolism v2.212 PDK3 Arina Puzriakova reviewed gene: PDK3: Rating: ; Mode of pathogenicity: None; Publications: 23297365, 26801680, 27388934, 28902413, 32504000, 34387338; Phenotypes: Charcot-Marie-Tooth disease, X-linked dominant, 6, OMIM:300905; 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 neuropathy or pain disorder v1.80 PDK3 Arina Puzriakova edited their review of gene: PDK3: Changed rating: GREEN
Hereditary neuropathy or pain disorder v1.80 PDK3 Arina Puzriakova Publications for gene: PDK3 were set to 26801680; 23297365
Hereditary neuropathy or pain disorder v1.79 PDK3 Arina Puzriakova Tag Q1_22_rating tag was added to gene: PDK3.
Hereditary neuropathy or pain disorder v1.79 PDK3 Arina Puzriakova Classified gene: PDK3 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.79 PDK3 Arina Puzriakova Added comment: Comment on list classification: At least two variants in three unrelated families reported (founder effect ruled out), as well as functional analyses conducted in patient fibroblasts, cell lines, and animal model. This supports a rating upgrade on this panel from Amber to Green at the next GMS panel update (tagged).
Hereditary neuropathy or pain disorder v1.79 PDK3 Arina Puzriakova Gene: pdk3 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.78 PDK3 Arina Puzriakova reviewed gene: PDK3: Rating: ; Mode of pathogenicity: None; Publications: 34387338; Phenotypes: Charcot-Marie-Tooth disease, X-linked dominant, 6, OMIM:300905; Mode of inheritance: None
Mitochondrial disorders v2.79 PDK3 Arina Puzriakova Mode of inheritance for gene: PDK3 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.503 AGR2 Arina Puzriakova Tag Q1_22_rating tag was added to gene: AGR2.
Primary ovarian insufficiency v1.63 KHDRBS1 Ivone Leong Classified gene: KHDRBS1 as Amber List (moderate evidence)
Primary ovarian insufficiency v1.63 KHDRBS1 Ivone Leong Added comment: Comment on list classification: This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:28938739 describes 2 cases. There was no details given for the idiopathic POI case.

ClinVar ID: 929733: as there is no further information available about this case I am hesitant in including this as part of the case count.

PMID:29808484. As stated by Zornitza Stark (Australian Genomics), the variant detected in this paper is also not included in the case count.

As there is only 1 case and 1 animal model there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating until more evidence is available.
Primary ovarian insufficiency v1.63 KHDRBS1 Ivone Leong Gene: khdrbs1 has been classified as Amber List (Moderate Evidence).
Primary ovarian insufficiency v1.62 KHDRBS1 Ivone Leong Tag watchlist tag was added to gene: KHDRBS1.
Retinal disorders v2.240 SSBP1 Sarah Leigh Tag Q1_22_MOI tag was added to gene: SSBP1.
Retinal disorders v2.240 SSBP1 Sarah Leigh reviewed gene: SSBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.56 SSBP1 Sarah Leigh changed review comment from: The moi for this gene could be changed to BOTH monoallelic and biallelic as PMID: 34905022 reports a case of SSBP1-disease with biallelic SSBP1 variants.; to: The moi for this gene should be changed to BOTH monoallelic and Biallelic as PMID: 34905022 & 3155024 report two cases of SSBP1-disease associated with biallelic SSBP1 variants. The variant c.380G>A p.(Arg127Gln)(MAF of 0.00004) was found with c.394A>G p.(Ile132Val)(PMID: 34905022), which had previously been found as a homozygote in a single case (PMID: 31550240).
Likely inborn error of metabolism v2.212 SSBP1 Sarah Leigh changed review comment from: Comment on mode of inheritance: The moi for this gene could be changed to BOTH monoallelic and Biallelic as PMID: 34905022 reports a case of SSBP1-disease with biallelic SSBP1 variants.; to: Comment on mode of inheritance: The moi for this gene should be changed to BOTH monoallelic and Biallelic as PMID: 34905022 & 3155024 report two cases of SSBP1-disease associated with biallelic SSBP1 variants. The variant c.380G>A p.(Arg127Gln)(MAF of 0.00004) was found with c.394A>G p.(Ile132Val)(PMID: 34905022), which had previously been found as a homozygote in a single case (PMID: 31550240).
Mitochondrial disorders v2.78 SSBP1 Sarah Leigh Tag Q1_22_MOI was removed from gene: SSBP1.
Mitochondrial disorders v2.78 SSBP1 Sarah Leigh edited their review of gene: SSBP1: Added comment: Associated with relevant phenotype in OMIM, but not associated with a phenotype in Gen2Phen.
SSBP1 is involved in mitochondrial biogenesis (PMID: 7789991) and variants in it are associated with mtDNA maintenance defects and mitochondrial disease. At least six heterozygous SSBP1 variants have been reported and two biallelic cases have also been reported; c.380G>A p.(Arg127Gln)(MAF of 0.00004) was found with c.394A>G p.(Ile132Val)(PMID: 34905022), which had previously been found as a homozygote in a single case (PMID: 31550240).; Changed rating: GREEN
Fetal anomalies v1.822 TLL1 Ivone Leong Tag Q1_22_rating tag was added to gene: TLL1.
Familial non syndromic congenital heart disease v1.71 TLL1 Ivone Leong Classified gene: TLL1 as Green List (high evidence)
Familial non syndromic congenital heart disease v1.71 TLL1 Ivone Leong Gene: tll1 has been classified as Green List (High Evidence).
Fetal anomalies v1.822 TLL1 Ivone Leong Entity copied from Familial non syndromic congenital heart disease v1.70
Fetal anomalies v1.822 TLL1 Ivone Leong gene: TLL1 was added
gene: TLL1 was added to Fetal anomalies. Sources: Expert Review Amber,Radboud University Medical Center, Nijmegen,Literature
Mode of inheritance for gene: TLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TLL1 were set to 18830233; 30538173; 27418595; 10331975; 31570783
Phenotypes for gene: TLL1 were set to Atrial septal defect 6, OMIM:613087
Penetrance for gene: TLL1 were set to Complete
Familial non syndromic congenital heart disease v1.70 TLL1 Ivone Leong Classified gene: TLL1 as Amber List (moderate evidence)
Familial non syndromic congenital heart disease v1.70 TLL1 Ivone Leong Gene: tll1 has been classified as Amber List (Moderate Evidence).
Familial non syndromic congenital heart disease v1.69 TLL1 Ivone Leong Classified gene: TLL1 as Green List (high evidence)
Familial non syndromic congenital heart disease v1.69 TLL1 Ivone Leong Added comment: Comment on list classification: This gene is associated with a phenotype in OMIM and Gene2Phenotype (limited). There is now enough evidence to support a gene-disease association. This gene should be rated Green.
Familial non syndromic congenital heart disease v1.69 TLL1 Ivone Leong Gene: tll1 has been classified as Green List (High Evidence).
Mitochondrial disorders v2.78 SSBP1 Sarah Leigh Classified gene: SSBP1 as Amber List (moderate evidence)
Mitochondrial disorders v2.78 SSBP1 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 v2.78 SSBP1 Sarah Leigh Gene: ssbp1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.77 SSBP1 Sarah Leigh Tag Q1_22_rating tag was added to gene: SSBP1.
Tag Q1_22_MOI tag was added to gene: SSBP1.
Familial non syndromic congenital heart disease v1.68 TLL1 Ivone Leong Added comment: Comment on publications: PMID:10331975 is a mouse model. Homozygous mutantsw were embryonic lethal with developmental defects in the heart (incomplete formation of the interventricular septum and an abnormal and novel positioning of the heart and aorta).

PMID:31570783 describes an individual with atrial septal defect with a de novo splice site variant in TLL1. However, the patient also has a variant in NODAL.
Familial non syndromic congenital heart disease v1.68 TLL1 Ivone Leong Publications for gene: TLL1 were set to 18830233; 30538173; 27418595
Primary immunodeficiency or monogenic inflammatory bowel disease v2.503 AGR2 Arina Puzriakova Classified gene: AGR2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.503 AGR2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.503 AGR2 Arina Puzriakova Gene: agr2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.502 AGR2 Arina Puzriakova Publications for gene: AGR2 were set to PMID: 34952832
Primary immunodeficiency or monogenic inflammatory bowel disease v2.501 AGR2 Arina Puzriakova Phenotypes for gene: AGR2 were changed from CF-like disorder to Cystic fibrosis-like syndrome
Optic neuropathy v2.56 SSBP1 Sarah Leigh reviewed gene: SSBP1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.56 SSBP1 Sarah Leigh Tag Q1_22_MOI tag was added to gene: SSBP1.
Likely inborn error of metabolism v2.212 SSBP1 Sarah Leigh Publications for gene: SSBP1 were set to 31298765; 31550240; 31550237; 30412255; 31479473; 31479473
Likely inborn error of metabolism v2.211 SSBP1 Sarah Leigh Added comment: Comment on mode of inheritance: The moi for this gene could be changed to BOTH monoallelic and Biallelic as PMID: 34905022 reports a case of SSBP1-disease with biallelic SSBP1 variants.
Likely inborn error of metabolism v2.211 SSBP1 Sarah Leigh Mode of inheritance for gene: SSBP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.210 SSBP1 Sarah Leigh Tag Q1_22_MOI tag was added to gene: SSBP1.
Childhood onset hereditary spastic paraplegia v2.121 PI4KA Arina Puzriakova Tag Q1_22_phenotype tag was added to gene: PI4KA.
Mitochondrial disorders v2.77 SSBP1 Sarah Leigh Added comment: Comment on mode of inheritance: PMID: 34905022 reports a case of SSBP1-disease with biallelic SSBP1 variants.
Mitochondrial disorders v2.77 SSBP1 Sarah Leigh Mode of inheritance for gene: SSBP1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v2.121 PI4KA Arina Puzriakova Tag Q1_22_expert_review tag was added to gene: PI4KA.
Tag Q1_22_NHS_review tag was added to gene: PI4KA.
Mitochondrial disorders v2.76 SSBP1 Sarah Leigh Mode of inheritance for gene: SSBP1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.56 SSBP1 Sarah Leigh Phenotypes for gene: SSBP1 were changed from Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510; Autosomal dominant optic atrophy with variable retinal degeneration; Optic atrophy with retinal degeneration (+-systemic features) to Optic atrophy 13 with retinal and foveal abnormalities OMIM:165510
Likely inborn error of metabolism v2.210 SSBP1 Sarah Leigh Publications for gene: SSBP1 were set to 31298765
Optic neuropathy v2.55 SSBP1 Sarah Leigh Publications for gene: SSBP1 were set to 31298765; 31550240; 31550237; 30412255
Likely inborn error of metabolism v2.209 SSBP1 Sarah Leigh Phenotypes for gene: SSBP1 were changed from to Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510
Mitochondrial disorders v2.75 SSBP1 Sarah Leigh Phenotypes for gene: SSBP1 were changed from No OMIM phenotype to Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510
Mitochondrial disorders v2.74 SSBP1 Sarah Leigh Publications for gene: SSBP1 were set to 29182774
Retinal disorders v2.240 SSBP1 Sarah Leigh Publications for gene: SSBP1 were set to 31298765; 31479473; 31550237; 31550240
Familial non syndromic congenital heart disease v1.67 TLL1 Ivone Leong Phenotypes for gene: TLL1 were changed from Atrial septal defect 6 613087 to Atrial septal defect 6, OMIM:613087
Familial non syndromic congenital heart disease v1.66 TLL1 Ivone Leong Publications for gene: TLL1 were set to 18830233
Intestinal failure or congenital diarrhoea v1.43 AGR2 Ivone Leong Entity copied from Respiratory ciliopathies including non-CF bronchiectasis v1.53
Intestinal failure or congenital diarrhoea v1.43 AGR2 Ivone Leong gene: AGR2 was added
gene: AGR2 was added to Intestinal failure. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: AGR2.
Mode of inheritance for gene: AGR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGR2 were set to 34952832
Phenotypes for gene: AGR2 were set to Cystic fibrosis-like syndrome; chronic diarrhoea
Penetrance for gene: AGR2 were set to Complete
Respiratory ciliopathies including non-CF bronchiectasis v1.53 AGR2 Ivone Leong Tag Q1_22_rating tag was added to gene: AGR2.
Respiratory ciliopathies including non-CF bronchiectasis v1.53 AGR2 Ivone Leong Classified gene: AGR2 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.53 AGR2 Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green.
Respiratory ciliopathies including non-CF bronchiectasis v1.53 AGR2 Ivone Leong Gene: agr2 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.52 AGR2 Ivone Leong Phenotypes for gene: AGR2 were changed from CF-like syndrome to Cystic fibrosis-like syndrome; chronic diarrhoea
Respiratory ciliopathies including non-CF bronchiectasis v1.51 AGR2 Ivone Leong Publications for gene: AGR2 were set to PMID: 34952832
Ataxia and cerebellar anomalies - narrow panel v2.280 PRDX3 Arina Puzriakova Entity copied from Hereditary ataxia - adult onset v2.138
Ataxia and cerebellar anomalies - narrow panel v2.280 PRDX3 Arina Puzriakova gene: PRDX3 was added
gene: PRDX3 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: PRDX3.
Mode of inheritance for gene: PRDX3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDX3 were set to 33889951
Phenotypes for gene: PRDX3 were set to Cerebellar ataxia (early onset, mild to moderate, progressive)
Hereditary ataxia with onset in adulthood v2.138 PRDX3 Arina Puzriakova Tag Q1_22_rating tag was added to gene: PRDX3.
Hereditary ataxia with onset in adulthood v2.138 PRDX3 Arina Puzriakova Classified gene: PRDX3 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v2.138 PRDX3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update.

Rebelo et al., 2021 (PMID: 33889951) reported five simplex families with biallelic variants in PRDX3 leading to complete loss of its encoded protein. Clinical presentation in all individuals predominantly consisted of gait and upper limb ataxia and cerebellar atrophy. Age of onset was at 13, 15, 21, 22 and 23 years of age. Pathogenicity supported by molecular studies using patient fibroblasts, cerebellar medulloblastoma cells and Drosophila.
Hereditary ataxia with onset in adulthood v2.138 PRDX3 Arina Puzriakova Gene: prdx3 has been classified as Amber List (Moderate Evidence).
Hereditary haemorrhagic telangiectasia v2.11 GDF2 Sarah Leigh Phenotypes for gene: GDF2 were changed from Telangiectasia, hereditary hemorrhagic, type 5 615506 to Telangiectasia, hereditary hemorrhagic, type 5 OMIM:615506; telangiectasia, hereditary hemorrhagic, type 5 MONDO:0014217
Primary immunodeficiency or monogenic inflammatory bowel disease v2.500 CARD10 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Rating Red at present only a single family has been reported as affected by immunodeficiency with autoimmunity due to a homozygoys variant in this gene (PMID: 32238915); to: Comment on list classification: New gene added by Zornitza Stark. Rating Red as at present only a single family has been reported as affected by immunodeficiency with autoimmunity due to a homozygoys variant in this gene (PMID: 32238915)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.500 CARD10 Arina Puzriakova Classified gene: CARD10 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.500 CARD10 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Red at present only a single family has been reported as affected by immunodeficiency with autoimmunity due to a homozygoys variant in this gene (PMID: 32238915)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.500 CARD10 Arina Puzriakova Gene: card10 has been classified as Red List (Low Evidence).
Hereditary haemorrhagic telangiectasia v2.10 GDF2 Sarah Leigh edited their review of gene: GDF2: Added comment: PMID: 34904380 reports a novel GDF2 variant (c.1282T>C, p.C428R) in three members of family displaying hereditary hemorrhagic telangiectasia (HHT) and pulmonary arteriovenous malformations. Functional studies support the delaterious effect of the variant in the normal cleavage of BMP9 proprotein, leading to an >2.5-fold lower level of the active mature dimer in the plasma of variant-positive family members in comparison to controls and lower levels of mature BMP9 from in vitro expression studies. There is phenotypic variability between patients carrying the same variant in HHT, and this is pronounced in the three cases reported in PMID: 34904380; although all of the cases in this familiy meet the Curaçao Criteria, the two non-proband cases are regarded as mild.; Changed rating: AMBER
Primary immunodeficiency or monogenic inflammatory bowel disease v2.499 CARD10 Arina Puzriakova Phenotypes for gene: CARD10 were changed from Immunodeficiency 89 and autoimmunity, MIM# 619632 to Immunodeficiency 89 and autoimmunity, OMIM:619632
Hereditary Erythrocytosis v1.44 PIEZO1 Arina Puzriakova Classified gene: PIEZO1 as Amber List (moderate evidence)
Hereditary Erythrocytosis v1.44 PIEZO1 Arina Puzriakova Added comment: Comment on list classification: New association with this phenotype identified by external reviewer, Dmitrijs Rots. Rating Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update.
Hereditary Erythrocytosis v1.44 PIEZO1 Arina Puzriakova Gene: piezo1 has been classified as Amber List (Moderate Evidence).
Hereditary Erythrocytosis v1.43 PIEZO1 Arina Puzriakova Tag Q1_22_rating tag was added to gene: PIEZO1.
Hereditary Erythrocytosis v1.43 PIEZO1 Arina Puzriakova reviewed gene: PIEZO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33181827, 31298594, 30655378; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary Erythrocytosis v1.43 PIEZO1 Arina Puzriakova Publications for gene: PIEZO1 were set to PMID: 33181827
Skeletal dysplasia v2.163 PRKG2 Arina Puzriakova Added comment: Comment on phenotypes: Added relevant phenotypes now listed in OMIM (MIM# 619636 and MIM# 619638)
Skeletal dysplasia v2.163 PRKG2 Arina Puzriakova Phenotypes for gene: PRKG2 were changed from acromesomelic dysplasia, MONDO:0019696; spondylometaphyseal dysplasia, MONDO:0016763 to Acromesomelic dysplasia 4, OMIM:619636; Spondylometaphyseal dysplasia, Pagnamenta type, OMIM:619638
Hereditary haemorrhagic telangiectasia v2.10 GDF2 Sarah Leigh Added comment: Comment on publications: 23972370 - 3 unrelated probands with no variants identified in ENG, ACVRL1, and SMAD4;27081547 - a variant of unknown significance in GDF2 was detected in one of 93 unrelated individuals clinically suspected to have HHT who previously tested negative for mutations in ENG, ACVRL1 and SMAD4;25674101 - review from the same authors as PMID:23972370
Hereditary haemorrhagic telangiectasia v2.10 GDF2 Sarah Leigh Publications for gene: GDF2 were set to 23972370 - 3 unrelated probands with no variants identified in ENG, ACVRL1, and SMAD4; 27081547 - a variant of unknown significance in GDF2 was detected in one of 93 unrelated individuals clinically suspected to have HHT who previously tested negative for mutations in ENG, ACVRL1 and SMAD4; 25674101 - review from the same authors as PMID:23972370; 32573726; 32669404; 33834622; https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A6356
Renal ciliopathies v1.45 DLG5 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: DLG5.
Respiratory ciliopathies including non-CF bronchiectasis v1.50 AGR2 Dmitrijs Rots gene: AGR2 was added
gene: AGR2 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: AGR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGR2 were set to PMID: 34952832
Phenotypes for gene: AGR2 were set to CF-like syndrome
Penetrance for gene: AGR2 were set to Complete
Review for gene: AGR2 was set to GREEN
Added comment: 13 individuals reported in PMID: 34952832 with Cystic fibrosis -like syndrome, including with respiratory infections, bronchiectasis etc. Ciliary abnormalities are reported, but authors suggest that they are likely secondary, similarly to CF.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.498 AGR2 Dmitrijs Rots gene: AGR2 was added
gene: AGR2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: AGR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGR2 were set to PMID: 34952832
Phenotypes for gene: AGR2 were set to CF-like disorder
Penetrance for gene: AGR2 were set to Complete
Review for gene: AGR2 was set to GREEN
Added comment: 13 individuals reported in PMID: 34952832 with Cystic Fibrosis like phenotype, including respiratory infections present in 13/13 individuals.
Sources: Literature
DDG2P v2.55 MYH6 Dmitrijs Rots reviewed gene: MYH6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v2.55 TERC Dmitrijs Rots reviewed gene: TERC: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v2.55 RMRP Dmitrijs Rots reviewed gene: RMRP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.55 COL6A1 Dmitrijs Rots reviewed gene: COL6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Bethlem myopathy, Ulrich myopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v2.55 PMS2 Dmitrijs Rots changed review comment from: DD is not part of the phenotype. Red on ID list.; to: DD is not part of the phenotype. Red on ID list. Other MMR deficiency genes are not in the panel.
DDG2P v2.55 PMS2 Dmitrijs Rots reviewed gene: PMS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
DDG2P v2.55 AR Dmitrijs Rots reviewed gene: AR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal and bulbar muscular atrophy, Androgen insensitivity syndrome; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Adult onset leukodystrophy v1.36 TPP2 Dmitrijs Rots edited their review of gene: TPP2: Changed rating: GREEN
Adult onset leukodystrophy v1.36 TPP2 Dmitrijs Rots changed review comment from: 14 individuals with "TRIANGLE" (TPPII-related immunodeficiency,
autoimmunity, and neurodevelopmental delay with impaired glycolysis
and lysosomal expansion) syndrome are summarized in 25414442, where 4/14 presented in adulthood with white matter leasions mimicking multiple sclerosis.
Sources: Literature; to: 14 individuals with "TRIANGLE" (TPPII-related immunodeficiency,
autoimmunity, and neurodevelopmental delay with impaired glycolysis
and lysosomal expansion) syndrome are summarized in 25414442, where 4/14 presented in adulthood with white matter leasions mimicking multiple sclerosis.
Should be rated green.
Sources: Literature
Adult onset leukodystrophy v1.36 TPP2 Dmitrijs Rots changed review comment from: 14 individuals with "TRIANGLE" (TPPII-related immunodeficiency,
autoimmunity, and neurodevelopmental delay with impaired glycolysis
and lysosomal expansion) syndrome are summarized in 25414442, where 4/14 presented in adulthood with white matter leasions mimicking multiple sclerosis.
Sources: Literature; to: 14 individuals with "TRIANGLE" (TPPII-related immunodeficiency,
autoimmunity, and neurodevelopmental delay with impaired glycolysis
and lysosomal expansion) syndrome are summarized in 25414442, where 4/14 presented in adulthood with white matter leasions mimicking multiple sclerosis.
Sources: Literature
Adult onset leukodystrophy v1.36 TPP2 Dmitrijs Rots gene: TPP2 was added
gene: TPP2 was added to White matter disorders - adult onset. Sources: Literature
Mode of inheritance for gene: TPP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPP2 were set to PMID:25414442
Phenotypes for gene: TPP2 were set to White matter abnormalities; autoimmunity; immunodefficiency; developmental delay
Added comment: 14 individuals with "TRIANGLE" (TPPII-related immunodeficiency,
autoimmunity, and neurodevelopmental delay with impaired glycolysis
and lysosomal expansion) syndrome are summarized in 25414442, where 4/14 presented in adulthood with white matter leasions mimicking multiple sclerosis.
Sources: Literature
DDG2P v2.55 TPP2 Dmitrijs Rots gene: TPP2 was added
gene: TPP2 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: TPP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPP2 were set to PMID: 25414442
Phenotypes for gene: TPP2 were set to Developmental delay; immunodefficiency; autoimmunity
Review for gene: TPP2 was set to GREEN
Added comment: 14 individuals with "TRIANGLE" (TPPII-related immunodeficiency,
autoimmunity, and neurodevelopmental delay with impaired glycolysis
and lysosomal expansion) syndrome are summarized in 25414442, where in 9/14 DD was present, which seems to be a common feature.
Sources: Literature
DDG2P v2.55 RASA1 Dmitrijs Rots reviewed gene: RASA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Familial non syndromic congenital heart disease v1.65 TLL1 Dmitrijs Rots reviewed gene: TLL1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30538173, 27418595; Phenotypes: Atrial septal defects; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.498 IKZF2 Boaz Palterer edited their review of gene: IKZF2: Changed publications to: 34826260, 34920454
Primary immunodeficiency or monogenic inflammatory bowel disease v2.498 IKZF2 Boaz Palterer gene: IKZF2 was added
gene: IKZF2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IKZF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IKZF2 were set to 34826260
Phenotypes for gene: IKZF2 were set to combined immunodeficiency; thrush; mucosal ulcers; chronic lymphoadenopathy; reduced MAIT cells
Penetrance for gene: IKZF2 were set to unknown
Added comment: Patients carrying the IKZF2 variant presented with a combined immunodeficiency phenotype characterized by recurrent upper respiratory infections, thrush and mucosal ulcers, and chronic lymphadenopathy. Reduced Helios expression was associated with chronic T cell activation and increased production of proinflammatory cytokines both in effector and regulatory T cells.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.498 RHBDF2 Boaz Palterer gene: RHBDF2 was added
gene: RHBDF2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: RHBDF2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: RHBDF2 were set to Pneumonia; Colitis; Immunodeficiency
Penetrance for gene: RHBDF2 were set to unknown
Review for gene: RHBDF2 was set to RED
Added comment: iRHOM deficiency with Respiratory and Intestinal inflammation and cytokine Secretion defect’ (IRIS): Kubo et al. (https://www.nature.com/articles/s41590-021-01093-y) described a new immunodeficiency disease due to loss-of-function mutations in RHBDF2, the gene encoding iRHOM2, in 4 subjects across two kindreds with recurrent infections in different organs. The disease presentation is pleiotropic, with one patient with recurrent pneumonia but no colon involvement, another had recurrent infectious hemorrhagic colitis but no lung involvement and the other two experienced recurrent respiratory infections. They replicated the phenotype in a KO mouse model and provided functional data.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.121 PI4KA Evan Reid commented on gene: PI4KA: This paper supports the idea that mutations in this gene can cause a relatively pure spastic paraplegia (PMID: 34415322 PMCID: PMC8557332 DOI: 10.1093/brain/awab124), which I think would justify inclusion of the gene on the HSP panel.
Childhood onset hereditary spastic paraplegia v2.121 PI4KA Evan Reid reviewed gene: PI4KA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34415322; Phenotypes: spastic paraplegia, leukodystrophy, white matter abnromality, seizures, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Differences in sex development v2.55 HHAT Eleanor Williams Phenotypes for gene: HHAT were changed from 46,XY DSD with chondrodysplasia to 46,XY DSD with chondrodysplasia; Nivelon-Nivelon-Mabille syndrome, OMIM:600092
Differences in sex development v2.54 HHAT Eleanor Williams Publications for gene: HHAT were set to 24784881
Differences in sex development v2.53 HHAT Eleanor Williams Classified gene: HHAT as Amber List (moderate evidence)
Differences in sex development v2.53 HHAT Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with a recommendation for green rating following GMS review. 2 cases reported with 46, XY karyotype and sex reversal, plus a supportive mouse model.
Differences in sex development v2.53 HHAT Eleanor Williams Gene: hhat has been classified as Amber List (Moderate Evidence).
Differences in sex development v2.52 HHAT Eleanor Williams Tag Q4_21_rating tag was added to gene: HHAT.
Differences in sex development v2.52 HHAT Eleanor Williams reviewed gene: HHAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 24784881, 30912300, 33749989; Phenotypes: Nivelon-Nivelon-Mabille syndrome, OMIM:600092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.276 HHAT Eleanor Williams Tag Q4_21_rating tag was added to gene: HHAT.
Severe microcephaly v2.276 HHAT Eleanor Williams Classified gene: HHAT as Amber List (moderate evidence)
Severe microcephaly v2.276 HHAT Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, with a recommendation for green rating following GMS review. 3 cases with microcephaly progressing to severe microcephaly reported.
Severe microcephaly v2.276 HHAT Eleanor Williams Gene: hhat has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.162 HHAT Eleanor Williams Classified gene: HHAT as Amber List (moderate evidence)
Skeletal dysplasia v2.162 HHAT Eleanor Williams Added comment: Comment on list classification: Promotion from grey to amber but with a recommendation for green rating following GMS review. 3 cases reported with a skeletal dysplasia phenotype and variants in HHAT.
Skeletal dysplasia v2.162 HHAT Eleanor Williams Gene: hhat has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.161 HHAT Eleanor Williams Tag Q4_21_rating tag was added to gene: HHAT.
Severe microcephaly v2.275 HHAT Eleanor Williams Entity copied from Skeletal dysplasia v2.161
Severe microcephaly v2.275 HHAT Eleanor Williams gene: HHAT was added
gene: HHAT was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HHAT were set to 24784881; 30912300; 33749989
Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome, OMIM:600092
Skeletal dysplasia v2.161 HHAT Eleanor Williams changed review comment from: Associated with Nivelon-Nivelon-Mabille syndrome #600092 (AR) in OMIM.

PMID:24784881 - Callier et al 2014 - report a family with 2 siblings with Disorder of Sex Development (DSD) and chondrodysplasia (Nivelon-Nivelon-Mabille syndrome). The first sibling (46,XY karyotype) displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly (-7.5 SD at age 16 (PMID:15578577) with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs. Complete gonadal dysgenesis and intellectual disability is also noted. The second sibling (46,XX karyotype) had histologically normal ovaries and similar phenotypic abnormalities including severe dwarfism and generalized chondrodysplasia. Using WES a homozygous missense variant was found NM_001122834:c.860G>T:p.(Gly287Val) in HHAT in the first sibling which is in the conserved MBOAT domain. The parents were heterozygous.

PMID:30912300 - Abdel-Salam et al 2019 - report two siblings with progressive microcephaly (-6 SD at age 6 and age 3 for the 2 siblings respectively), early infantile onset seizures, and cerebellar vermis hypoplasia but notably without dwarfism and gonadal dysgenesis. Skeletal x-rays of both siblings showed nlarged epiphyses and metaphyses, thinning of the lateral 1/3 of clavicles and trapezoidal vertebral bodies. WES found a homozygous missense (c.770T>C, p.[Leu257Pro]) HHAT which is in the conserved MBOAT domain. Both parents were heterozygous for the variant.

PMID: 33749989 - Pande et al 2021 - report multiple malformations in three pregnancies with a novel biallelic in-frame deletion, c.365_367del; (p.Thr122del), in exon 5 of HHAT in the living proband. She shows severe microphthalmia, microcephaly (−8 SD head circumference at age 7), skeletal dysplasia (narrow bell-shaped tho-rax, short and angel-shaped epiphyses of hands and feet) and midfac eretrusion, short columella with a groove at the base, prominent ears, long philtrum, depressed nasal bridge, everted lower lip, and a singlec entral incisor. She also has complete sex reversal (karyotype of 46, XY, normal internal organs including uterus and ovaries.); to: Associated with Nivelon-Nivelon-Mabille syndrome #600092 (AR) in OMIM.

PMID:24784881 - Callier et al 2014 - report a family with 2 siblings with Disorder of Sex Development (DSD) and chondrodysplasia (Nivelon-Nivelon-Mabille syndrome). The first sibling (46,XY karyotype) displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly (-7.5 SD at age 16 (PMID:15578577) with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs. Complete gonadal dysgenesis ( including normal external female genitalia, lack of pubertal development, primary amenorrhea, and hypergonadotrophic hypogonadism) and intellectual disability is also noted. The second sibling (46,XX karyotype) had histologically normal ovaries and similar phenotypic abnormalities including severe dwarfism and generalized chondrodysplasia. Using WES a homozygous missense variant was found NM_001122834:c.860G>T:p.(Gly287Val) in HHAT in the first sibling which is in the conserved MBOAT domain. The parents were heterozygous. They also found that mice lacking functional Hhat show a similar phenotype as the syndromic 46,XY DSD patient including testicular dysgenesis and skeletal defects.

PMID:30912300 - Abdel-Salam et al 2019 - report two siblings with progressive microcephaly (-6 SD at age 6 and age 3 for the 2 siblings respectively), early infantile onset seizures, and cerebellar vermis hypoplasia but notably without dwarfism and gonadal dysgenesis. Skeletal x-rays of both siblings showed enlarged epiphyses and metaphyses, thinning of the lateral 1/3 of clavicles and trapezoidal vertebral bodies. Both sisters had a normal female karyotype (46, XX). WES found a homozygous missense (c.770T>C, p.[Leu257Pro]) HHAT which is in the conserved MBOAT domain. Both parents were heterozygous for the variant.

PMID: 33749989 - Pande et al 2021 - report multiple malformations in three pregnancies with a novel biallelic in-frame deletion, c.365_367del; (p.Thr122del), in exon 5 of HHAT in the living proband. She shows severe microphthalmia, microcephaly (−8 SD head circumference at age 7), skeletal dysplasia (narrow bell-shaped tho-rax, short and angel-shaped epiphyses of hands and feet) and midfac eretrusion, short columella with a groove at the base, prominent ears, long philtrum, depressed nasal bridge, everted lower lip, and a singlec entral incisor. She also has complete sex reversal (karyotype of 46, XY, normal internal organs including uterus and ovaries.)
Skeletal dysplasia v2.161 HHAT Eleanor Williams Phenotypes for gene: HHAT were changed from Nivelon-Nivelon-Mabille syndrome 600092 to Nivelon-Nivelon-Mabille syndrome, OMIM:600092
Skeletal dysplasia v2.160 HHAT Eleanor Williams Publications for gene: HHAT were set to 24784881; 30912300
Skeletal dysplasia v2.159 HHAT Eleanor Williams reviewed gene: HHAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 24784881, 30912300, 33749989; Phenotypes: Nivelon-Nivelon-Mabille syndrome, OMIM:600092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v1.59 MIB1 Ivone Leong Tag Q2_21_NHS_review was removed from gene: MIB1.
Skeletal ciliopathies v1.15 PDIA6 Eleanor Williams Classified gene: PDIA6 as Amber List (moderate evidence)
Skeletal ciliopathies v1.15 PDIA6 Eleanor Williams Added comment: Comment on list classification: Promoted from grey to amber. 1 case plus functional data.
Skeletal ciliopathies v1.15 PDIA6 Eleanor Williams Gene: pdia6 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v1.14 PDIA6 Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM. In Gene2Phenotype it is associated with PDIA6-associated syndromic neonatal diabetes and asphyxiating thoracic dystrophy with Limited confidence.

As Zornitza Stark reports PMID: 33495992 (Al-Fadhli et al 2021) describes one case of a child with asphyxiating thoracic dystrophy (ATD) syndrome and infantile-onset diabetes who had a homozygous frameshift variant in the PDIA6 gene (NM_001282704.1:c.703del (p.Val235fs)) which is in exon 8 (of 15). The parents and unaffected sibling were heterozygous for this variant. The authors state that PDIA6 is not known yet to be involved in the formation or function of the primary cilia but suggest that it could be directly or indirectly interacting or required for proper protein folding of known or unknown ciliopathy protein. The X-ray findings at 6 months were consistent with typical radiological features of ATD syndrome.; to: Not associated with a phenotype in OMIM. In Gene2Phenotype it is associated with PDIA6-associated syndromic neonatal diabetes and asphyxiating thoracic dystrophy with Limited confidence.

As Zornitza Stark reports PMID: 33495992 (Al-Fadhli et al 2021) describes one case of a child with asphyxiating thoracic dystrophy (ATD) syndrome and infantile-onset diabetes who had a homozygous frameshift variant in the PDIA6 gene (NM_001282704.1:c.703del (p.Val235fs)) which is in exon 8 (of 15). The parents and unaffected sibling were heterozygous for this variant. The authors state that PDIA6 is not known yet to be involved in the formation or function of the primary cilia but suggest that it could be directly or indirectly interacting or required for proper protein folding of known or unknown ciliopathy protein.

The X-ray findings at 6 months were consistent with typical radiological features of ATD syndrome. Other features include intrauterine growth retardation, multiple cysts in both kidneys associated with renal oligohydramnios (in first antenatal ultrasound) and hyperglycemia on the second day of life.
Skeletal ciliopathies v1.14 PDIA6 Eleanor Williams commented on gene: PDIA6
Skeletal ciliopathies v1.14 CSPP1 Eleanor Williams Classified gene: CSPP1 as Amber List (moderate evidence)
Skeletal ciliopathies v1.14 CSPP1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating following GMS review. 3 cases reported with a skeletal phenotype.
Skeletal ciliopathies v1.14 CSPP1 Eleanor Williams Gene: cspp1 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v1.13 CSPP1 Eleanor Williams Tag Q4_21_rating tag was added to gene: CSPP1.
Skeletal ciliopathies v1.13 CSPP1 Eleanor Williams Phenotypes for gene: CSPP1 were changed from Joubert syndrome 21, MIM# 615636 to Joubert syndrome 21, OMIM:615636; Joubert syndrome with Jeune asphyxiating thoracic dystrophy, MONDO:0018342
Skeletal ciliopathies v1.12 CSPP1 Eleanor Williams Publications for gene: CSPP1 were set to 24360808
Skeletal ciliopathies v1.11 CSPP1 Eleanor Williams reviewed gene: CSPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24360808, 24360803; Phenotypes: Joubert syndrome 21, OMIM:615636, Joubert syndrome with Jeune asphyxiating thoracic dystrophy, MONDO:0018342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.137 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms, 268800; Sandhoff disease, 268800 to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Early onset or syndromic epilepsy v2.483 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms, 268800; seizures; myoclonic epilepsy to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Familial pulmonary fibrosis v1.18 ACD Øystein Holla gene: ACD was added
gene: ACD was added to Familial pulmonary fibrosis. Sources: Literature
Mode of inheritance for gene: ACD was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ACD were set to 31515401
Phenotypes for gene: ACD were set to dyskeratosis congenita, telomere disorder, pulmonary fibrosis
Penetrance for gene: ACD were set to unknown
Review for gene: ACD was set to GREEN
gene: ACD was marked as current diagnostic
Added comment: Pathogenic variants in ACD cause dyskeratosis congenita (DC) and short telomeres.
People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis.
(GeneReviews Dyskeratosis Congenita, Last Revision: November 21, 2019.)

Unaffected heterozygotes are reported, PMID: 33446513
Sources: Literature
Malformations of cortical development v2.129 RAB3GAP2 Sarah Leigh Phenotypes for gene: RAB3GAP2 were changed from Warburg micro syndrome 2, OMIM:614225 to Warburg micro syndrome 2, OMIM:614225; Warburg micro syndrome 2 MONDO:0013641
Malformations of cortical development v2.128 RAB3GAP2 Sarah Leigh Publications for gene: RAB3GAP2 were set to 23420520; 20967465
Malformations of cortical development v2.127 RAB3GAP2 Sarah Leigh Tag Q4_21_rating tag was added to gene: RAB3GAP2.
Malformations of cortical development v2.127 RAB3GAP2 Sarah Leigh edited their review of gene: RAB3GAP2: Added comment: Associated with relevant phenotype in OMIM, but not associated with Warburg micro syndrome 2 OMIM:614225 in Gen2Phen. At least four variants reported in at least four unrelated cases..; Changed rating: GREEN
Severe microcephaly v2.274 TP53RK Eleanor Williams edited their review of gene: TP53RK: Changed rating: GREEN
Malformations of cortical development v2.127 RAB3GAP2 Sarah Leigh Classified gene: RAB3GAP2 as Amber List (moderate evidence)
Malformations of cortical development v2.127 RAB3GAP2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Malformations of cortical development v2.127 RAB3GAP2 Sarah Leigh Gene: rab3gap2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.126 RAB3GAP1 Sarah Leigh Publications for gene: RAB3GAP1 were set to 23420520; 32740904
Malformations of cortical development v2.125 RAB3GAP1 Sarah Leigh edited their review of gene: RAB3GAP1: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least 13 variants reported in at least 12 unrelated cases; Changed rating: GREEN
Malformations of cortical development v2.125 RAB3GAP1 Sarah Leigh Phenotypes for gene: RAB3GAP1 were changed from Warburg micro syndrome 1, OMIM:600118 to Warburg micro syndrome 1 OMIM:600118; Warburg micro syndrome 1 MONDO:0010822
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 B3GAT3 Eleanor Williams Tag Q3_21_NHS_review tag was added to gene: B3GAT3.
Malformations of cortical development v2.124 RAB3GAP1 Sarah Leigh Tag Q4_21_rating tag was added to gene: RAB3GAP1.
Malformations of cortical development v2.124 RAB3GAP1 Sarah Leigh Classified gene: RAB3GAP1 as Amber List (moderate evidence)
Malformations of cortical development v2.124 RAB3GAP1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Malformations of cortical development v2.124 RAB3GAP1 Sarah Leigh Gene: rab3gap1 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.123 DAG1 Sarah Leigh Classified gene: DAG1 as Green List (high evidence)
Malformations of cortical development v2.123 DAG1 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.
Malformations of cortical development v2.123 DAG1 Sarah Leigh Gene: dag1 has been classified as Green List (High Evidence).
Malformations of cortical development v2.122 DAG1 Sarah Leigh reviewed gene: DAG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v2.159 MESD Eleanor Williams Tag Q3_21_NHS_review tag was added to gene: MESD.
Malformations of cortical development v2.122 DAG1 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: DAG1.
Malformations of cortical development v2.122 DAG1 Sarah Leigh Publications for gene: DAG1 were set to 24052401; 25934851
Malformations of cortical development v2.121 DAG1 Sarah Leigh Publications for gene: DAG1 were set to 24052401
Malformations of cortical development v2.120 PTEN Sarah Leigh edited their review of gene: PTEN: Added comment: In the retrospective study PMID: 32162846, the authors observe four unrelated cases who exhibit polymicrogyria.; Changed rating: GREEN
Malformations of cortical development v2.120 PTEN Sarah Leigh Tag Q4_21_rating tag was added to gene: PTEN.
Malformations of cortical development v2.120 PTEN Sarah Leigh Classified gene: PTEN as Amber List (moderate evidence)
Malformations of cortical development v2.120 PTEN Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Malformations of cortical development v2.120 PTEN Sarah Leigh Gene: pten has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.119 PTEN Sarah Leigh Phenotypes for gene: PTEN were changed from Cowden syndrome 1 158350; Lhermitte-Duclos syndrome 158350; Macrocephaly/autism syndrome 605309 to Cowden syndrome 1 OMIM:158350; Lhermitte-Duclos syndrome OMIM:158350; Cowden syndrome 1 MONDO:0008021; Macrocephaly/autism syndrome OMIM:605309; macrocephaly-autism syndrome MONDO:0011537
Adult onset leukodystrophy v1.36 CTC1 Ivone Leong Tag Q3_21_expert_review tag was added to gene: CTC1.
Hereditary ataxia with onset in adulthood v2.136 B4GAT1 Ivone Leong Tag Q3_21_rating tag was added to gene: B4GAT1.
Adult onset hereditary spastic paraplegia v1.88 SERAC1 Ivone Leong Tag Q3_21_phenotype tag was added to gene: SERAC1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 HNRNPK Ivone Leong Tag Q3_21_rating tag was added to gene: HNRNPK.
White matter disorders and cerebral calcification - narrow panel v1.220 PTEN Ivone Leong Tag Q3_21_rating tag was added to gene: PTEN.
White matter disorders and cerebral calcification - narrow panel v1.220 ERCC1 Ivone Leong Tag Q3_21_rating tag was added to gene: ERCC1.
Skeletal dysplasia v2.159 PRKG2 Eleanor Williams Tag Q4_21_NHS_review tag was added to gene: PRKG2.
Ataxia and cerebellar anomalies - narrow panel v2.279 ALDH5A1 Ivone Leong Tag Q3_21_rating tag was added to gene: ALDH5A1.
Hypogonadotropic hypogonadism v1.33 SPRY4 Ivone Leong Tag Q2_21_expert_review was removed from gene: SPRY4.
Hypogonadotropic hypogonadism (GMS) v1.48 SPRY4 Ivone Leong Entity copied from Hypogonadotropic hypogonadism v1.33
Hypogonadotropic hypogonadism (GMS) v1.48 SPRY4 Ivone Leong gene: SPRY4 was added
gene: SPRY4 was added to Hypogonadotropic hypogonadism idiopathic. Sources: Expert Review Amber,Radboud University Medical Center, Nijmegen,Expert list,Literature
monogenic-polygenic, Q2_21_expert_review tags were added to gene: SPRY4.
Mode of inheritance for gene: SPRY4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPRY4 were set to 23643382; 32389901
Phenotypes for gene: SPRY4 were set to Hypogonadotropic hypogonadism 17 with or without anosmia, OMIM:615266
Penetrance for gene: SPRY4 were set to Complete
Congenital disorders of glycosylation v2.78 TMEM199 Ivone Leong Tag Q3_21_rating tag was added to gene: TMEM199.
Hereditary neuropathy or pain disorder v1.78 MME Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: MME.
Hereditary neuropathy or pain disorder v1.78 MME Arina Puzriakova Added comment: Comment on mode of inheritance: Heterozygous variants have been identified in >10 individuals with late-onset CMT2T. However, some variants have been found in control databases and family studies indicate incomplete penetrance, suggesting heterozygous variants only confer susceptibility. Nonetheless, sufficient cases have been reported in literature and both MOIs are listed in OMIM for this phenotype, and so inclusion of monoallelic inheritance on this panel will first be flagged for GMS review.
Hereditary neuropathy or pain disorder v1.78 MME Arina Puzriakova Mode of inheritance for gene: MME was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.77 MME Arina Puzriakova Tag adult-onset tag was added to gene: MME.
Tag Q4_21_MOI tag was added to gene: MME.
Adult onset leukodystrophy v1.36 AARS Ivone Leong Tag Q2_21_rating was removed from gene: AARS.
Tag Q4_21_expert_review tag was added to gene: AARS.
Adult onset leukodystrophy v1.36 AARS Ivone Leong Tag Q2_21_rating tag was added to gene: AARS.
Hereditary neuropathy v1.432 MME Arina Puzriakova Publications for gene: MME were set to 26991897; 27588448
Hereditary neuropathy or pain disorder v1.77 MME Arina Puzriakova Publications for gene: MME were set to 26991897; 27588448
Hereditary neuropathy v1.431 MME Arina Puzriakova Phenotypes for gene: MME were changed from Charcot-Marie-Tooth disease, axonal, type 2T, 617017 to Charcot-Marie-Tooth disease, axonal, type 2T, OMIM:617017
Hereditary neuropathy or pain disorder v1.76 MME Arina Puzriakova Phenotypes for gene: MME were changed from Charcot-Marie-Tooth disease, axonal, type 2T, 617017 to Charcot-Marie-Tooth disease, axonal, type 2T, OMIM:617017
Likely inborn error of metabolism v2.208 TARS2 Sarah Leigh Classified gene: TARS2 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.208 TARS2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism v2.208 TARS2 Sarah Leigh Gene: tars2 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.207 TARS2 Sarah Leigh Tag Q4_21_rating tag was added to gene: TARS2.
Hereditary ataxia with onset in adulthood v2.136 MME Arina Puzriakova Publications for gene: MME were set to
Hereditary ataxia with onset in adulthood v2.135 MME Arina Puzriakova Phenotypes for gene: MME were changed from Spinocerebellar ataxia type 43, 617018 to ?Spinocerebellar ataxia 43, OMIM:617018
Childhood onset dystonia, chorea or related movement disorder v1.209 TARS2 Sarah Leigh Tag Q4_21_rating tag was added to gene: TARS2.
Childhood onset dystonia, chorea or related movement disorder v1.209 TARS2 Sarah Leigh Classified gene: TARS2 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.209 TARS2 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 v1.209 TARS2 Sarah Leigh Gene: tars2 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.208 TARS2 Sarah Leigh Classified gene: TARS2 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.208 TARS2 Sarah Leigh Gene: tars2 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.207 TARS2 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 11 variants reported in at least 7 unrelated cases with a varied phenotype, including encephalomyopathy, epilepsy, dystonia, hyperhidrosis and severe hearing impairment. Supportive functional studies were also presented PMID: 34508595.; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 11 variants reported in at least 7 unrelated cases with a varied phenotype, including encephalomyopathy, epilepsy, dystonia, hyperhidrosis and severe hearing impairment. At least three unrelated cases of dystonia reported. Supportive functional studies were also presented PMID: 34508595.
Childhood onset dystonia, chorea or related movement disorder v1.207 TARS2 Sarah Leigh Publications for gene: TARS2 were set to
Hereditary neuropathy or pain disorder v1.75 MME Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: MME.
Childhood onset dystonia, chorea or related movement disorder v1.206 TARS2 Sarah Leigh Mode of inheritance for gene: TARS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.62 TARS2 Sarah Leigh Phenotypes for gene: TARS2 were changed from ?Combined oxidative phosphorylation deficiency 21, 615918 to Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21 MONDO:0014398
Likely inborn error of metabolism v2.207 TARS2 Sarah Leigh Phenotypes for gene: TARS2 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); ?Combined oxidative phosphorylation deficiency 21, 615918 to Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21 MONDO:0014398
Possible mitochondrial disorder - nuclear genes v1.61 TARS2 Sarah Leigh Publications for gene: TARS2 were set to
Likely inborn error of metabolism v2.206 TARS2 Sarah Leigh Added comment: Comment on publications: PMID: 24827421 - Compound heterozygous variants in TARS2 were reported in the proband and his affected sister - a missense mutation (c.845C>T, p.Pro282Leu) and a nucleotide change in position +3 of intron 6 (g.4255A>G, c.695+3A>G). The parents carrying one of the variants, one unaffected sister carried one variant, and the other unaffected sibling carried neither.
Likely inborn error of metabolism v2.206 TARS2 Sarah Leigh Publications for gene: TARS2 were set to PMID: 24827421 - Compound heterozygous variants in TARS2 were reported in the proband and his affected sister - a missense mutation (c.845C>T, p.Pro282Leu) and a nucleotide change in position +3 of intron 6 (g.4255A>G, c.695+3A>G). The parents carrying one of the variants, one unaffected sister carried one variant, and the other unaffected sibling carried neither.
Likely inborn error of metabolism v2.205 TARS2 Sarah Leigh reviewed gene: TARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33153448, 24827421, 34508595; Phenotypes: Combined oxidative phosphorylation deficiency 21 OMIM:615918, combined oxidative phosphorylation defect type 21 MONDO:0014398; Mode of inheritance: None
Possible mitochondrial disorder - nuclear genes v1.60 TARS2 Sarah Leigh reviewed gene: TARS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33153448, 24827421, 34508595; Phenotypes: Combined oxidative phosphorylation deficiency 21 OMIM:615918, combined oxidative phosphorylation defect type 21 MONDO:0014398; Mode of inheritance: None
Childhood onset dystonia, chorea or related movement disorder v1.205 TARS2 Sarah Leigh reviewed gene: TARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33153448, 24827421, 34508595; Phenotypes: Combined oxidative phosphorylation deficiency 21 OMIM:615918, combined oxidative phosphorylation defect type 21 MONDO:0014398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.73 TARS2 Sarah Leigh Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21MONDO:0014398 to Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21 MONDO:0014398
Mitochondrial disorders v2.72 TARS2 Sarah Leigh Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21MONDO:0014398 to Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21MONDO:0014398
Mitochondrial disorders v2.72 TARS2 Sarah Leigh Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21 OMIM:615918 to Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21MONDO:0014398
Amyotrophic lateral sclerosis/motor neuron disease v1.49 KIF5A Andrey Gagunashvili gene: KIF5A was added
gene: KIF5A was added to Amyotrophic lateral sclerosis/motor neuron disease. Sources: Literature
Mode of inheritance for gene: KIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KIF5A were set to 29566793; 29342275; 30581417; 33077544; 34873335
Phenotypes for gene: KIF5A were set to Amyotrophic lateral sclerosis
Penetrance for gene: KIF5A were set to unknown
Review for gene: KIF5A was set to GREEN
Added comment: "...mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases." (Nicolas et al., 2018)
Sources: Literature
Renal ciliopathies v1.45 IFT140 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as biallelic for now, but with a recommendation that it should be updated to BOTH monoallelic and biallelic following GMS review.
Renal ciliopathies v1.45 IFT140 Eleanor Williams Mode of inheritance for gene: IFT140 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Renal ciliopathies v1.44 IFT140 Eleanor Williams Phenotypes for gene: IFT140 were changed from Short-rib thoracic dysplasia 9 with or without polydactyly, OMIM #266920 (aka Mainzer-Saldino syndrome) to Short-rib thoracic dysplasia 9 with or without polydactyly, OMIM:266920; short-rib thoracic dysplasia 9 with or without polydactyly, MONDO:0009964; cystic kidney disease, MONDO:0002473
Renal ciliopathies v1.43 IFT140 Eleanor Williams Publications for gene: IFT140 were set to PMID: 22503633, 23418020, 29706353
Renal ciliopathies v1.42 IFT140 Eleanor Williams Tag Q4_21_MOI tag was added to gene: IFT140.
Tag Q4_21_NHS_review tag was added to gene: IFT140.
Renal ciliopathies v1.42 IFT140 Eleanor Williams reviewed gene: IFT140: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.71 TARS2 Sarah Leigh edited their review of gene: TARS2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 11 variants reported in at least 7 unrelated cases with a varied phenotype, including encephalomyopathy, epilepsy, dystonia, hyperhidrosis and severe hearing impairment.; Changed rating: GREEN
Mitochondrial disorders v2.71 TARS2 Sarah Leigh Tag Q4_21_rating tag was added to gene: TARS2.
Mitochondrial disorders v2.71 TARS2 Sarah Leigh Classified gene: TARS2 as Amber List (moderate evidence)
Mitochondrial disorders v2.71 TARS2 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 v2.71 TARS2 Sarah Leigh Gene: tars2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.70 TARS2 Sarah Leigh Phenotypes for gene: TARS2 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); ?Combined oxidative phosphorylation deficiency 21, 615918 to Combined oxidative phosphorylation deficiency 21 OMIM:615918
Mitochondrial disorders v2.69 TARS2 Sarah Leigh Added comment: Comment on publications: PMID: 24827421 - Compound heterozygous variants in TARS2 were reported in the proband and his affected sister - a missense mutation (c.845C>T, p.Pro282Leu) and a nucleotide change in position +3 of intron 6 (g.4255A>G, c.695+3A>G). The parents carrying one of the variants, one unaffected sister carried one variant, and the other unaffected sibling carried neither.
Mitochondrial disorders v2.69 TARS2 Sarah Leigh Publications for gene: TARS2 were set to PMID: 24827421 - Compound heterozygous variants in TARS2 were reported in the proband and his affected sister - a missense mutation (c.845C>T, p.Pro282Leu) and a nucleotide change in position +3 of intron 6 (g.4255A>G, c.695+3A>G). The parents carrying one of the variants, one unaffected sister carried one variant, and the other unaffected sibling carried neither.
Arthrogryposis v3.145 SLC6A9 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: SLC6A9.
Skeletal dysplasia v2.159 ZNF687 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: ZNF687.
Hypertrophic cardiomyopathy v2.32 GYG1 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: GYG1.
Proteinuric renal disease v2.61 LCAT Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: LCAT.
Hereditary neuropathy or pain disorder v1.75 C1orf194 Arina Puzriakova Tag Q3_21_rating tag was added to gene: C1orf194.
Unexplained young onset end-stage renal disease v1.23 TRIM8 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: TRIM8.
Ichthyosis and erythrokeratoderma v1.69 ALDH3A2 Arina Puzriakova Tag Q3_21_NHS_review tag was added to gene: ALDH3A2.
Childhood onset hereditary spastic paraplegia v2.121 HPDL Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: HPDL.
Childhood onset dystonia, chorea or related movement disorder v1.205 C9orf72 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: C9orf72.
Early onset or syndromic epilepsy v2.482 UFSP2 Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: UFSP2.
Hereditary ataxia with onset in adulthood v2.134 VPS41 Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: VPS41.
Adult onset dystonia, chorea or related movement disorder v1.161 VPS41 Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: VPS41.
Ataxia and cerebellar anomalies - narrow panel v2.279 VPS41 Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: VPS41.
Cystic kidney disease v2.27 FLCN Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: FLCN.
Intellectual disability v3.1484 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms, 268800; GM2-GANGLIOSIDOSIS TYPE 2 (GM2G2) to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Likely inborn error of metabolism v2.205 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms, 268800 to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Fetal anomalies v1.821 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from GM2-GANGLIOSIDOSIS TYPE 2 to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Undiagnosed metabolic disorders v1.503 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms 268800 to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Adult onset neurodegenerative disorder v2.258 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms, 268800 to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Hereditary ataxia v1.281 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms, 268800 to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Ataxia and cerebellar anomalies - narrow panel v2.279 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms, 268800 to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Hereditary neuropathy or pain disorder v1.75 HEXB Arina Puzriakova Tag Q4_21_rating tag was added to gene: HEXB.
Hereditary neuropathy or pain disorder v1.75 HEXB Arina Puzriakova Publications for gene: HEXB were set to 17015493; 20472204; 20798201; 2795083; 31512525; 34856081
Hereditary neuropathy or pain disorder v1.74 HEXB Arina Puzriakova Publications for gene: HEXB were set to PMID: 31512525
Hereditary neuropathy or pain disorder v1.73 HEXB Arina Puzriakova Classified gene: HEXB as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.73 HEXB Arina Puzriakova Added comment: Comment on list classification: Neuropathy has been described in Sandhoff disease, particularly in adult-onset cases where this can be an initial finding and other symptoms may be more mild. Sufficient unrelated cases of neuropathy due to variants in this gene have been reported in literature (>3). Overall HEXB should be promoted to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v1.73 HEXB Arina Puzriakova Gene: hexb has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.72 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Hereditary neuropathy or pain disorder v1.71 HEXA Arina Puzriakova Publications for gene: HEXA were set to PMID: 28739864; 18642377
Hereditary neuropathy or pain disorder v1.70 HEXA Arina Puzriakova Tag Q4_21_rating tag was added to gene: HEXA.
Hereditary neuropathy or pain disorder v1.70 HEXA Arina Puzriakova Classified gene: HEXA as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.70 HEXA Arina Puzriakova Added comment: Comment on list classification: Neuronopathy and peripheral neuropathy have been described in Tay-Sachs disease, particularly in adult-onset cases where this can be an initial finding and other symptoms may be more mild. Sufficient unrelated cases of neuropathy due to variants in this gene have been reported in literature (>3). Overall HEXA should be promoted to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v1.70 HEXA Arina Puzriakova Gene: hexa has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.69 HEXA Arina Puzriakova Phenotypes for gene: HEXA were changed from to Tay-Sachs disease, OMIM:272800; Late-onset Tay-Sachs disease
Intellectual disability v3.1483 ATAD1 Ivone Leong Phenotypes for gene: ATAD1 were changed from Hyperekplexia 4, MIM#618011 to Hyperekplexia 4, OMIM:618011
Intellectual disability v3.1482 ATAD1 Ivone Leong Publications for gene: ATAD1 were set to 28180185
Malformations of cortical development v2.118 RAB3GAP1 Ivone Leong Added comment: Comment on publications: More cases PMID: 32740904
Malformations of cortical development v2.118 RAB3GAP1 Ivone Leong Publications for gene: RAB3GAP1 were set to 23420520
Malformations of cortical development v2.117 RAB3GAP1 Ivone Leong Phenotypes for gene: RAB3GAP1 were changed from Warburg micro syndrome 1, MIM# 600118 to Warburg micro syndrome 1, OMIM:600118
Malformations of cortical development v2.116 RAB18 Ivone Leong Tag Q4_21_rating tag was added to gene: RAB18.
Malformations of cortical development v2.116 RAB18 Ivone Leong Classified gene: RAB18 as Amber List (moderate evidence)
Malformations of cortical development v2.116 RAB18 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (Definitive). There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Malformations of cortical development v2.116 RAB18 Ivone Leong Gene: rab18 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.820 KIDINS220 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: KIDINS220.
Malformations of cortical development v2.115 RAB18 Ivone Leong Phenotypes for gene: RAB18 were changed from Warburg micro syndrome 3, MIM# 614222 to Warburg micro syndrome 3, OMIM:614222
Malformations of cortical development v2.114 NPRL3 Ivone Leong Tag Q4_21_rating tag was added to gene: NPRL3.
Malformations of cortical development v2.114 NPRL3 Ivone Leong Classified gene: NPRL3 as Amber List (moderate evidence)
Malformations of cortical development v2.114 NPRL3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be given a Green rating at the next review.
Malformations of cortical development v2.114 NPRL3 Ivone Leong Gene: nprl3 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.113 NPRL3 Ivone Leong Phenotypes for gene: NPRL3 were changed from Epilepsy, familial focal, with variable foci 3 (MIM#617118) to Epilepsy, familial focal, with variable foci 3, OMIM:617118
Intellectual disability v3.1481 KCND2 Eleanor Williams Classified gene: KCND2 as Amber List (moderate evidence)
Intellectual disability v3.1481 KCND2 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with a recommendation for green rating following GMS review. 3 cases reported with missense variants in this gene with no seizures, plus further cases with seizures.
Intellectual disability v3.1481 KCND2 Eleanor Williams Gene: kcnd2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1480 KCND2 Eleanor Williams Tag Q4_21_rating tag was added to gene: KCND2.
Intellectual disability v3.1480 KCND2 Eleanor Williams gene: KCND2 was added
gene: KCND2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KCND2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCND2 were set to 34245260; 16934482; 24501278
Phenotypes for gene: KCND2 were set to global developmental delay, HP:0001263
Mode of pathogenicity for gene: KCND2 was set to Other
Added comment: 6 new unrelated cases with developmental delay reported in PMID: 34245260 (Zhang et al 2021), 3 of whom had seizures. All had heterozygous missense variants of KCND2 in sites known to be critical for channel gating (E323K, P403A, two individuals, V404L, two individuals and V404M). Functional studies suggest that these missense changes cause both a partial loss-of-function (LOF) and gain-of-function (GOF). The V404 change appears to increase epileptic seizure susceptibility with the 3 patients with a V404 change showing this phenotype.

PMID:16934482 - Singh et al, 2006 - reports a patient with cognitive impairment who also went on to have seizures starting from age 13 with a 5 bp deletion in KCND2 leading to premature stop codon. The proband's asymptomatic father also shared this variant.

Also:
PMID:24501278 - Lee et al, 2014 - reports pair of monozygotic twin boys with infantile onset severe refractory epilepsy and autism. A de novo heterozygous missense variant was identified by WES - V404M.
Sources: Literature
Early onset or syndromic epilepsy v2.482 KCND2 Eleanor Williams changed review comment from: 6 new unrelated cases with developmental delay reported in PMID: 34245260 (Zhang et al 2021), 3 of whom had seizures. All had heterozygous missense variants of KCND2 in sites known to be critical for channel gating (E323K, P403A, two individuals, V404L, two individuals and V404M). Functional studies suggest that these missense changes cause both a partial loss-of-function (LOF) and gain-of-function (GOF). The V404 change appears to increase epileptic seizure susceptibility with the 3 patients with a V404 change showing this phenotype.; to: 6 new unrelated cases with developmental delay reported in PMID: 34245260 (Zhang et al 2021), 3 of whom had seizures. All had heterozygous missense variants of KCND2 in sites known to be critical for channel gating (E323K, P403A, two individuals, V404L, two individuals and V404M). Functional studies suggest that these missense changes cause both a partial loss-of-function (LOF) and gain-of-function (GOF). The V404 change appears to increase epileptic seizure susceptibility with the 3 patients with a V404 change showing this phenotype.

PMID:24501278 - Lee et al, 2014 - reports pair of monozygotic twin boys with infantile onset severe refractory epilepsy and autism. A de novo heterozygous missense variant was identified by WES - V404M.

PMID: 29581270 - Lin et al, 2018 - performed functional work that shows V404M enhances inactivation of channels that have not yet opened and dramatically impairs the inactivation of channels that have opened.

PMID:16934482 - Singh et al, 2006 - reports a patient with cognative impairment who also went on to have seizures starting from age 13 with a 5 bp deletion in KCND2 leading to premature stop codon. The proband's asymptomatic father also shared this variant.
Early onset or syndromic epilepsy v2.482 KCND2 Eleanor Williams Classified gene: KCND2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.482 KCND2 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber with a recommendation for green rating following GMS review. 4 unrelated cases with a V404 missense variant and epilepsy.
Early onset or syndromic epilepsy v2.482 KCND2 Eleanor Williams Gene: kcnd2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.481 KCND2 Eleanor Williams Phenotypes for gene: KCND2 were changed from epilepsy; seizures to epilepsy, NBO:0000642; seizure, HP:0001250
Early onset or syndromic epilepsy v2.480 KCND2 Eleanor Williams Phenotypes for gene: KCND2 were changed from epilepsy; autism to epilepsy; seizures
Early onset or syndromic epilepsy v2.479 KCND2 Eleanor Williams Publications for gene: KCND2 were set to 24501278; 16934482; 29581270
Early onset or syndromic epilepsy v2.478 KCND2 Eleanor Williams Tag Q4_21_rating tag was added to gene: KCND2.
Early onset or syndromic epilepsy v2.478 KCND2 Eleanor Williams reviewed gene: KCND2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34245260; Phenotypes: seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Renal ciliopathies v1.42 IFT140 John Sayer reviewed gene: IFT140: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1016/j.ajhg.2021.11.016; Phenotypes: Cystic kidney disease, cystic liver disease; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary Erythrocytosis v1.42 SH2B3 Arina Puzriakova changed review comment from: Eligibility criteria for this panel states that secondary causes of erythrocytosis such as myeloproliferative neoplasm must be excluded prior to testing.; to: Eligibility criteria for this panel (R405) states that secondary causes of erythrocytosis such as myeloproliferative neoplasm must be excluded prior to testing.
Hereditary Erythrocytosis v1.42 SH2B3 Arina Puzriakova commented on gene: SH2B3
Hereditary Erythrocytosis v1.42 SLC30A10 Arina Puzriakova Publications for gene: SLC30A10 were set to PMID: 22341971; 22341972
Hereditary Erythrocytosis v1.41 SLC30A10 Arina Puzriakova Classified gene: SLC30A10 as Amber List (moderate evidence)
Hereditary Erythrocytosis v1.41 SLC30A10 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by external reviewer Dmitrijs Rots. There is enough evidence to promote this gene to Green at the next GMS panel update. All affected individuals reported to date (>3) had polycythemia at the time of diagnosis, which can precede the onset of neurologic manifestations and therefore it is worth including SLC30A10 on this panel.
Hereditary Erythrocytosis v1.41 SLC30A10 Arina Puzriakova Gene: slc30a10 has been classified as Amber List (Moderate Evidence).
Hereditary Erythrocytosis v1.40 SLC30A10 Arina Puzriakova Tag treatable tag was added to gene: SLC30A10.
Tag Q4_21_rating tag was added to gene: SLC30A10.
Hereditary Erythrocytosis v1.40 SLC30A10 Arina Puzriakova Phenotypes for gene: SLC30A10 were changed from Erythrocytosis; Polycytemia; Hypermanganesemia; Parkinsonism; Dystonia; Liver disease to Hypermanganesemia with dystonia 1, OMIM:613280; Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease
Likely inborn error of metabolism v2.204 SLC30A10 Arina Puzriakova Phenotypes for gene: SLC30A10 were changed from Parkinson Disease and Complex Parkinsonism; Early onset dystonia; Hypermanganesemia with dystonia 1; Hypermanganesemia with dystonia, polycythemia, and cirrhosis (Disorder of magnesium metabolism) to Hypermanganesemia with dystonia 1, OMIM:613280
Childhood onset dystonia, chorea or related movement disorder v1.205 SLC30A10 Arina Puzriakova Phenotypes for gene: SLC30A10 were changed from Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease; Hypermanganesemia with dystonia, polycythemia, and cirrhosis, 613280 to Hypermanganesemia with dystonia 1, OMIM:613280
Undiagnosed metabolic disorders v1.502 SLC30A10 Arina Puzriakova Phenotypes for gene: SLC30A10 were changed from Hypermanganesemia with dystonia, polycythemia, and cirrhosis (Disorder of magnesium metabolism); Early onset dystonia; Parkinson Disease and Complex Parkinsonism; Hypermanganesemia with dystonia 1 613280 to Hypermanganesemia with dystonia 1, OMIM:613280
Structural basal ganglia disorders v1.27 SLC30A10 Arina Puzriakova Phenotypes for gene: SLC30A10 were changed from to Hypermanganesemia with dystonia 1, OMIM:613280
Neonatal cholestasis v1.21 SLC30A10 Arina Puzriakova Phenotypes for gene: SLC30A10 were changed from Hypermanganesemia with dystonia 1 613280 to Hypermanganesemia with dystonia 1, OMIM:613280
Early onset dystonia v1.103 SLC30A10 Arina Puzriakova Phenotypes for gene: SLC30A10 were changed from Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, andChronic Liver Disease; Hypermanganesemia with dystonia, polycythemia, and cirrhosis, 613280 to Hypermanganesemia with dystonia 1, OMIM:613280; Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease
Parkinson Disease and Complex Parkinsonism v1.93 SLC30A10 Arina Puzriakova Phenotypes for gene: SLC30A10 were changed from Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease; Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, andChronic Liver Disease; hypermanganesemia with dystonia-1 (HMNDYT1), increased serum manganese, motor neurodegeneration with extrapyramidal features, polycythemia, and hepatic dysfunction, Brain MRI shows hyperintensities in the basal ganglia to Hypermanganesemia with dystonia 1, OMIM:613280; Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease
Mitochondrial disorders v2.68 OGDH Sarah Leigh Phenotypes for gene: OGDH were changed from Alpha-ketoglutarate dehydrogenase deficiency, 203740 (1) to Alpha-ketoglutarate dehydrogenase deficiency OMIM:203740; oxoglutaricaciduria MONDO:0008759
Mitochondrial disorders v2.67 OGDH Sarah Leigh Mode of inheritance for gene: OGDH was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.66 OGDH Sarah Leigh Classified gene: OGDH as Amber List (moderate evidence)
Mitochondrial disorders v2.66 OGDH Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM. Limited association with OGDH-related mitochondrial disorder in Gen2Phen. PMID: 32383294 reported a single biallelic variant in two sibblings. Functional studies were performed on patient fibroblasts, which demonstrated reduced expression of OGDH and a reduced OGDH complex activity in comparison to the wild type. Drosophila models were constructed which supported the role of the OGDH variant in early developmental lethality.
Mitochondrial disorders v2.66 OGDH Sarah Leigh Gene: ogdh has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.65 OGDH Sarah Leigh Publications for gene: OGDH were set to
Mitochondrial disorders v2.64 KIAA0391 Sarah Leigh commented on gene: KIAA0391: PRORP is the HGNC approved gene name for KIAA0391 https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:19958
Mitochondrial disorders v2.64 KIAA0391 Sarah Leigh Tag Q4_21_rating tag was added to gene: KIAA0391.
Mitochondrial disorders v2.64 KIAA0391 Sarah Leigh Classified gene: KIAA0391 as Amber List (moderate evidence)
Mitochondrial disorders v2.64 KIAA0391 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 v2.64 KIAA0391 Sarah Leigh Gene: kiaa0391 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.63 KIAA0391 Sarah Leigh reviewed gene: KIAA0391: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Perrault syndrome clinical spectrum; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.63 KIAA0391 Sarah Leigh Tag new-gene-name tag was added to gene: KIAA0391.
Early onset dystonia v1.102 ACTB Sarah Leigh Classified gene: ACTB as Green List (high evidence)
Early onset dystonia v1.102 ACTB Sarah Leigh Added comment: Comment on list classification: Based on the green rating for this gene on https://panelapp.genomicsengland.co.uk/panels/847/gene/ACTB/ and review from Eldar Dedic.
Early onset dystonia v1.102 ACTB Sarah Leigh Gene: actb has been classified as Green List (High Evidence).
Hereditary neuropathy or pain disorder v1.68 MME Lindsey Vialard reviewed gene: MME: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27588448, 33144514; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset dystonia v1.101 ACTB Sarah Leigh Phenotypes for gene: ACTB were changed from Dystonia, juvenile-onset, 607371Baraitser-Winter syndrome 1, 243310 to Dystonia, juvenile-onset OMIM:607371; developmental malformations-deafness-dystonia syndrome MONDO:0011823; Baraitser-Winter syndrome 1 OMIM:243310; Baraitser-Winter syndrome 1 MONDO:0009470
Early onset dystonia v1.100 ACTB Sarah Leigh Publications for gene: ACTB were set to
Bilateral congenital or childhood onset cataracts v2.94 TCF4 Sarah Leigh Classified gene: TCF4 as Red List (low evidence)
Bilateral congenital or childhood onset cataracts v2.94 TCF4 Sarah Leigh Added comment: Comment on list classification: Single case of paediatric cateracts
Bilateral congenital or childhood onset cataracts v2.94 TCF4 Sarah Leigh Gene: tcf4 has been classified as Red List (Low Evidence).
Bilateral congenital or childhood onset cataracts v2.93 TCF4 Sarah Leigh Added comment: Comment on phenotypes: Variants in TCF4 are associated with Corneal dystrophy, Fuchs endothelial, 3, OMIM:613267, however, this condition does not include cataracts, which associated with TCF4 trinucleotide repeat (RCV000186552.6) in https://doi.org/10.3390/genes12121918.
Bilateral congenital or childhood onset cataracts v2.93 TCF4 Sarah Leigh Phenotypes for gene: TCF4 were changed from Corneal dystrophy, Fuchs endothelial, 3, OMIM:613267 to paediatric cataracts
Bilateral congenital or childhood onset cataracts v2.92 TCF4 Sarah Leigh Publications for gene: TCF4 were set to 29526280; 26401622; 24255041; 25168903; 25722209; 25593321
Bilateral congenital or childhood onset cataracts v2.91 TCF4 Sarah Leigh edited their review of gene: TCF4: Added comment: In https://doi.org/10.3390/genes12121918 (no PMID number available as of 9th December 2021) the authors report TCF4 trinucleotide repeat (RCV000186552.6) in a case Kearns-Sayre Syndrome and corneal endothelial failure and paediatric cataracts.; Changed rating: AMBER; Changed publications to: https://doi.org/10.3390/genes12121918; Changed phenotypes to: paediatric cataracts
Bilateral congenital or childhood onset cataracts v2.91 TCF4 Sarah Leigh Entity copied from Corneal dystrophies v1.8
Bilateral congenital or childhood onset cataracts v2.91 TCF4 Sarah Leigh gene: TCF4 was added
gene: TCF4 was added to Cataracts. Sources: Expert Review Green,Expert list
STR tags were added to gene: TCF4.
Mode of inheritance for gene: TCF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TCF4 were set to 29526280; 26401622; 24255041; 25168903; 25722209; 25593321
Phenotypes for gene: TCF4 were set to Corneal dystrophy, Fuchs endothelial, 3, OMIM:613267
Corneal dystrophy v1.8 TCF4 Sarah Leigh changed review comment from: Comment on publications: Also https://doi.org/10.3390/genes12121918 (no PMID available 30th Dec 2021).; to: Comment on publications: Also https://doi.org/10.3390/genes12121918 (no PMID available 30th Nov 2021).
Primary lymphoedema v2.23 ANGPT2 Sarah Leigh edited their review of gene: ANGPT2: Changed rating: AMBER
Fetal hydrops v1.45 ANGPT2 Sarah Leigh Tag for-review was removed from gene: ANGPT2.
Fetal hydrops v1.45 ANGPT2 Sarah Leigh Classified gene: ANGPT2 as Amber List (moderate evidence)
Fetal hydrops v1.45 ANGPT2 Sarah Leigh Added comment: Comment on list classification: One biallelic variant in four sibblings in a single family with severe early-onset non-immune hydrops fetalis (pmid 34876502).
Fetal hydrops v1.45 ANGPT2 Sarah Leigh Gene: angpt2 has been classified as Amber List (Moderate Evidence).
Fetal hydrops v1.45 ANGPT2 Sarah Leigh Classified gene: ANGPT2 as Amber List (moderate evidence)
Fetal hydrops v1.45 ANGPT2 Sarah Leigh Added comment: Comment on list classification: One biallelic variant in four sibblings in a single family with severe early-onset non-immune hydrops fetalis (pmid 34876502).
Fetal hydrops v1.45 ANGPT2 Sarah Leigh Gene: angpt2 has been classified as Amber List (Moderate Evidence).
Fetal hydrops v1.44 ANGPT2 Sarah Leigh Entity copied from Primary lymphoedema v2.23
Fetal hydrops v1.44 ANGPT2 Sarah Leigh gene: ANGPT2 was added
gene: ANGPT2 was added to Fetal hydrops. Sources: Expert Review Amber,Literature
for-review tags were added to gene: ANGPT2.
Mode of inheritance for gene: ANGPT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANGPT2 were set to 32908006; 34876502
Phenotypes for gene: ANGPT2 were set to Lymphatic malformation 10 OMIM:619369; lymphatic malformation 10 MONDO:0023662
Primary lymphoedema v2.23 ANGPT2 Sarah Leigh edited their review of gene: ANGPT2: Added comment: PMID 34876502 reports four fetuses with hydrops fetalis were homozygous for ANGPT2 NM_001147.2:c.557A>G. The consanguiseious parents and surviving sibblings (a girl and a boy), were heterozygous for this variant. This variant is predicted to create a cryptic exonic splice site, resulting in a r.557_566del and nonsense-mediated mRNA decay. This prediction was supported by the lack of a transcript from this allele in the parents.; Changed rating: GREEN; Changed publications to: 34876502; Changed phenotypes to: severe early-onset non-immune hydrops fetalis; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary lymphoedema v2.23 ANGPT2 Sarah Leigh Publications for gene: ANGPT2 were set to 32908006
Primary lymphoedema v2.22 ANGPT2 Sarah Leigh Added comment: Comment on phenotypes: Biallelic variants reported in severe early-onset non-immune hydrops fetalis (PMID 34876502).
Primary lymphoedema v2.22 ANGPT2 Sarah Leigh Phenotypes for gene: ANGPT2 were changed from Lymphatic malformation 10 OMIM:619369; lymphatic malformation 10 MONDO:0023662 to Lymphatic malformation 10 OMIM:619369; lymphatic malformation 10 MONDO:0023662
Primary lymphoedema v2.21 ANGPT2 Sarah Leigh Phenotypes for gene: ANGPT2 were changed from Primary lymphoedema to Lymphatic malformation 10 OMIM:619369; lymphatic malformation 10 MONDO:0023662
Early onset dystonia v1.99 GCDH Eldar Dedic reviewed gene: GCDH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 21912879, 33064266; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary Erythrocytosis v1.39 PIEZO1 Arina Puzriakova Phenotypes for gene: PIEZO1 were changed from Erythrocytosis to Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, OMIM:194380; Erythrocytosis
Primary lymphoedema v2.20 PIEZO1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Both mono- and biallelic' to 'Biallelic' only at the next GMS review. Monoallelic variants are associated with hereditary xerocytosis (MIM# 194380), a phenotype that is not relevant to this panel.
Primary lymphoedema v2.20 PIEZO1 Arina Puzriakova Mode of inheritance for gene: PIEZO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary lymphoedema v2.19 PIEZO1 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: PIEZO1.
Primary lymphoedema v2.19 PIEZO1 Arina Puzriakova Phenotypes for gene: PIEZO1 were changed from Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema 194380; Lymphatic malformation 6 616843 to Lymphatic malformation 6, OMIM:616843
Rare anaemia v1.31 PIEZO1 Arina Puzriakova Phenotypes for gene: PIEZO1 were changed from Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, OMIM:194380; Lymphatic malformation 6, OMIM:616843; Hereditary xerocytosis to Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, OMIM:194380; Hereditary xerocytosis
Rare anaemia v1.30 PIEZO1 Arina Puzriakova Phenotypes for gene: PIEZO1 were changed from 194380 Stomatocytosis; 616843 Lymphatic malformation 6; 194380 Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema; Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema; Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, 194380; Stomatocytosis; Hereditary xerocytosis; Dehydrated hereditary stomatocytosis to Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, OMIM:194380; Lymphatic malformation 6, OMIM:616843; Hereditary xerocytosis
Cytopenias and congenital anaemias v1.93 PIEZO1 Arina Puzriakova Phenotypes for gene: PIEZO1 were changed from Stomatocytosis; Dehydrated hereditary stomatocytosis; Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, 194380; Hereditary xerocytosis to Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, OMIM:194380; Hereditary xerocytosis
Fetal anomalies v1.820 PIEZO1 Arina Puzriakova Phenotypes for gene: PIEZO1 were changed from hydrops fetalis gene 616843; Congenital lymphatic dysplasia with hydrops and/or lymphoedema to Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, OMIM:194380; Lymphatic malformation 6, OMIM:616843; Congenital lymphatic dysplasia with hydrops and/or lymphoedema
Fetal hydrops v1.43 PIEZO1 Arina Puzriakova Phenotypes for gene: PIEZO1 were changed from Lymphedema, hereditary, III, 616843; LMPH3; Hereditary lymphoedema type III; 2nd trimester fetal hydrops, Nuchal translucency likely to be normal, Lethal and non lethal cases within the same family to Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, OMIM:194380; Lymphatic malformation 6, OMIM:616843; Congenital lymphatic dysplasia with hydrops and/or lymphoedema
Hereditary Erythrocytosis v1.38 SH2B3 Arina Puzriakova Publications for gene: SH2B3 were set to 23812944; 20843259
Hereditary Erythrocytosis v1.37 BPGM Arina Puzriakova Publications for gene: BPGM were set to 27651169; 25015942; 5799137; 1421379; 15054810
Hereditary Erythrocytosis v1.36 BPGM Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: BPGM.
Tag Q4_21_MOI tag was added to gene: BPGM.
Tag Q4_21_rating tag was added to gene: BPGM.
Hereditary Erythrocytosis v1.36 BPGM Arina Puzriakova Added comment: Comment on mode of inheritance: Three patients described in literature with biallelic variants (PMID: 1421379; 15054810; 33216349) and 2 with heterozygous variants (PMID: 25015942; 27651169) in the BPGM gene. Heterozygous variants in some cases may cause milder erythrocytosis due to partial BPGM deficiency.

Of the four individuals (2 homo, 2 het) identified in the paper reviewed by Dmitrijs Rots (PMID: 29790589), three variants were classified VUS and the other had been previously reported and therefore these cases could not be included.

Although the number of monoallelic cases does not reach the threshold for inclusion, the evidence supports an association with erythrocytosis. To reduce risk of potentially missed diagnoses the MOI may be considered for update from 'biallelic' to 'both mono- and biallelic' but this will be flagged for further GMS review.

In any case, BPGM should be promoted to Green at the next GMS panel update with the respective MOI based on the decision of the expert working group.
Hereditary Erythrocytosis v1.36 BPGM Arina Puzriakova Mode of inheritance for gene: BPGM was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v1.50 POLR2C Ivone Leong Phenotypes for gene: POLR2C were changed from Primary ovarian insufficiency to thrombocytopenia, MONDO:0002049
Cytopenias and congenital anaemias v1.92 POLR2C Ivone Leong Phenotypes for gene: POLR2C were changed from thrombocytopenia, to thrombocytopenia, MONDO:0002049
Cytopenias and congenital anaemias v1.91 POLR2C Ivone Leong Phenotypes for gene: POLR2C were changed from thrombocytopenia, to thrombocytopenia,
Cytopenias and congenital anaemias v1.91 POLR2C Ivone Leong Phenotypes for gene: POLR2C were changed from Primary ovarian insufficiency to thrombocytopenia,
Congenital hypothyroidism v2.8 POLR2C Ivone Leong Phenotypes for gene: POLR2C were changed from Primary ovarian insufficiency to hypothyroidism, MONDO:0005420
Congenital hypothyroidism v2.7 POLR2C Ivone Leong Classified gene: POLR2C as Red List (low evidence)
Congenital hypothyroidism v2.7 POLR2C Ivone Leong Gene: polr2c has been classified as Red List (Low Evidence).
Congenital hypothyroidism v2.6 POLR2C Ivone Leong Tag watchlist was removed from gene: POLR2C.
Congenital hypothyroidism v2.6 POLR2C Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. The affected patients in PMID: 29367954 also had hypothyroidism (3/5), thrombocytopenia (2/5) and pernicious anaemia (2/5).; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. The affected patients in PMID: 29367954 also had hypothyroidism (3/5), thrombocytopenia (2/5) and pernicious anaemia (2/5). The entries in ClinVar did not mention any other phenotype. So therefore this gene has been given a Red rating.
Cytopenia - NOT Fanconi anaemia v1.49 POLR2C Ivone Leong Classified gene: POLR2C as Red List (low evidence)
Cytopenia - NOT Fanconi anaemia v1.49 POLR2C Ivone Leong Gene: polr2c has been classified as Red List (Low Evidence).
Cytopenia - NOT Fanconi anaemia v1.48 POLR2C Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. The affected patients in PMID: 29367954 also had hypothyroidism (3/5), thrombocytopenia (2/5) and pernicious anaemia (2/5).; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. The affected patients in PMID: 29367954 also had hypothyroidism (3/5), thrombocytopenia (2/5) and pernicious anaemia (2/5). The entries in ClinVar did not mention any other phenotype. So therefore this gene has been given a Red rating.
Cytopenia - NOT Fanconi anaemia v1.48 POLR2C Ivone Leong Tag watchlist was removed from gene: POLR2C.
Cytopenias and congenital anaemias v1.90 POLR2C Ivone Leong Classified gene: POLR2C as Red List (low evidence)
Cytopenias and congenital anaemias v1.90 POLR2C Ivone Leong Gene: polr2c has been classified as Red List (Low Evidence).
Primary ovarian insufficiency v1.62 POLR2C Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. The affected patients in PMID: 29367954 also had hypothyroidism (3/5), thrombocytopenia (2/5) and pernicious anaemia (2/5).; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. The affected patients in PMID: 29367954 also had hypothyroidism (3/5), thrombocytopenia (2/5) and pernicious anaemia (2/5). There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Cytopenias and congenital anaemias v1.89 POLR2C Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. The affected patients in PMID: 29367954 also had hypothyroidism (3/5), thrombocytopenia (2/5) and pernicious anaemia (2/5).; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. The affected patients in PMID: 29367954 also had hypothyroidism (3/5), thrombocytopenia (2/5) and pernicious anaemia (2/5). The entries in ClinVar did not mention any other phenotype. So therefore this gene has been given a Red rating.
Cytopenias and congenital anaemias v1.89 POLR2C Ivone Leong Tag watchlist was removed from gene: POLR2C.
Cytopenias and congenital anaemias v1.89 POLR2C Ivone Leong Entity copied from Primary ovarian insufficiency v1.62
Cytopenias and congenital anaemias v1.89 POLR2C Ivone Leong gene: POLR2C was added
gene: POLR2C was added to Cytopenias and congenital anaemias. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: POLR2C.
Mode of inheritance for gene: POLR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR2C were set to 34794894; 29367954
Phenotypes for gene: POLR2C were set to Primary ovarian insufficiency
Cytopenia - NOT Fanconi anaemia v1.48 POLR2C Ivone Leong Entity copied from Primary ovarian insufficiency v1.62
Cytopenia - NOT Fanconi anaemia v1.48 POLR2C Ivone Leong gene: POLR2C was added
gene: POLR2C was added to Cytopenia - NOT Fanconi anaemia. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: POLR2C.
Mode of inheritance for gene: POLR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR2C were set to 34794894; 29367954
Phenotypes for gene: POLR2C were set to Primary ovarian insufficiency
Congenital hypothyroidism v2.6 POLR2C Ivone Leong Entity copied from Primary ovarian insufficiency v1.62
Congenital hypothyroidism v2.6 POLR2C Ivone Leong gene: POLR2C was added
gene: POLR2C was added to Congenital hypothyroidism. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: POLR2C.
Mode of inheritance for gene: POLR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR2C were set to 34794894; 29367954
Phenotypes for gene: POLR2C were set to Primary ovarian insufficiency
Primary ovarian insufficiency v1.62 POLR2C Ivone Leong Classified gene: POLR2C as Amber List (moderate evidence)
Primary ovarian insufficiency v1.62 POLR2C Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. The affected patients in PMID: 29367954 also had hypothyroidism (3/5), thrombocytopenia (2/5) and pernicious anaemia (2/5).
Primary ovarian insufficiency v1.62 POLR2C Ivone Leong Gene: polr2c has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.68 RFC1 Eleanor Williams commented on gene: RFC1: Copied this gene from the Hereditary ataxia - adult onset panel so that it is noted that the STR associated with this gene is relevant to the panel, NOT SNV/indels or deletions covering this gene. In PMID: 33969391 - Curro et al 2021 - they found that 43 patients (34%) with sensory neuropathy had biallelic AAGGG repeat expansions in RFC1and in none with sensory-motor neuropathy.
Primary ovarian insufficiency v1.61 POLR2C Ivone Leong Tag watchlist tag was added to gene: POLR2C.
Hereditary neuropathy or pain disorder v1.68 RFC1 Eleanor Williams Entity copied from Hereditary ataxia - adult onset v2.134
Hereditary neuropathy or pain disorder v1.68 RFC1 Eleanor Williams gene: RFC1 was added
gene: RFC1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Expert Review Red,Expert Review
STR tags were added to gene: RFC1.
Mode of inheritance for gene: RFC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFC1 were set to 30926972; 31824583; 32851396; 32582864; 33969391
Phenotypes for gene: RFC1 were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM:614575; cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, MONDO:0013809; chronic idiopathic axonal polyneuropathy; chronic polyneuropathy, MONDO:0003335
Mode of pathogenicity for gene: RFC1 was set to Other
Hereditary ataxia with onset in adulthood v2.134 RFC1 Eleanor Williams Classified gene: RFC1 as Red List (low evidence)
Hereditary ataxia with onset in adulthood v2.134 RFC1 Eleanor Williams Added comment: Comment on list classification: Changing the rating from amber to red so that it is clear that this gene should not be added to the panel as it is an STR within an intron of this gene that is associated with the neuropathy phenotype.
Hereditary ataxia with onset in adulthood v2.134 RFC1 Eleanor Williams Gene: rfc1 has been classified as Red List (Low Evidence).
DDG2P v2.55 PBX1 Eleanor Williams Classified gene: PBX1 as No list
DDG2P v2.55 PBX1 Eleanor Williams Added comment: Comment on list classification: Changing the status to Expert Review Removed, as the content of the panel is only changed when updated from DDG2P sources. The status of this gene on other panels has been checked.
DDG2P v2.55 PBX1 Eleanor Williams Gene: pbx1 has been removed from the panel.
DDG2P v2.54 PBX1 Eleanor Williams Tag curated_removed tag was added to gene: PBX1.
DDG2P v2.54 PBX1 Eleanor Williams Classified gene: PBX1 as No list
DDG2P v2.54 PBX1 Eleanor Williams Gene: pbx1 has been removed from the panel.
DDG2P v2.53 PBX1 Eleanor Williams commented on gene: PBX1
Monogenic hearing loss v2.214 PBX1 Eleanor Williams Publications for gene: PBX1 were set to 28566479; 29036646
Monogenic hearing loss v2.213 PBX1 Eleanor Williams Mode of inheritance for gene: PBX1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.212 PBX1 Eleanor Williams Tag Q4_21_rating tag was added to gene: PBX1.
Monogenic hearing loss v2.212 PBX1 Eleanor Williams changed review comment from: Comment on list classification: Promoting from grey to amber. 3 cases but in 1 case 7 other genes also deleted, and in another hearing loss was unilateral only.; to: Comment on list classification: Promoting from grey to amber. Deletions affecting more than just the PBX1 gene is reported for many, but in 3 cases only the PBX1 gene is affected. Recommend green rating following GMS review.
Monogenic hearing loss v2.212 PBX1 Eleanor Williams changed review comment from: Associated with Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay #617641 (AD) in OMIM.

3 cases with reported hearing loss among other anomalies, but in one case a further 7 genes are deleted, and in one case the hearing loss was unilateral only.

PMID: 28566479 - Heidet et al 2017 - performed targeted exome screening of candidate 330 genes in a cohort of 204 patients with CAKUT and 11 patients suspected to suffer from branchio-oto-renal syndrome. 2 out of 5 patients with heterozygous loss of function mutations/deletions in PBX1 are reported to have deafness in addition to a renal phenotype. In patient K175 there was a de novo heterozygous 1 bp deletion leading to a frameshift. In patient K1819 there was a de novo 2.46-Mb deletion removing the whole PBX1 gene along with 7 other genes. Further details about the loss of hearing phenotype are not given.

PMID: 29036646 - Slavotinek et al 2017 - report 8 patients with de novo, deleterious sequence variants in the PBX1. 3 had external ear abnormalities but only 1 is reported to have hearing loss and this is unilateral, mild to moderate conductive hearing loss. This patient was found to have a heterozygous, de novo indel c.783dupC, predicting (p.Ser262Glnfs*2 in PBX1.; to: Associated with Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay #617641 (AD) in OMIM.

3 cases reported where only the PBX1 gene is affected (indels or deletion covering only the PBX1 gene). In one of these cases the phenotype is syndromic but hearing loss is unilateral only. In 5 further cases hearing loss is reported and involve microdeletions covering more genes that just PBX1.

PMID: 28566479 - Heidet et al 2017 - performed targeted exome screening of candidate 330 genes in a cohort of 204 patients with CAKUT and 11 patients suspected to suffer from branchio-oto-renal syndrome. 2 out of 5 patients with heterozygous loss of function mutations/deletions in PBX1 are reported to have deafness in addition to a renal phenotype. In patient K175 there was a de novo heterozygous 1 bp deletion leading to a frameshift. In patient K1819 there was a de novo 2.46-Mb deletion removing the whole PBX1 gene along with 7 other genes. Further details about the loss of hearing phenotype are not given.

PMID: 29036646 - Slavotinek et al 2017 - report 8 patients with de novo, deleterious sequence variants in the PBX1. 3 had external ear abnormalities but only 1 is reported to have hearing loss and this is unilateral, mild to moderate conductive hearing loss. This patient was found to have a heterozygous, de novo indel c.783dupC, predicting (p.Ser262Glnfs*2 in PBX1.

PMID: 28270404 - Le Tanno et al 2017 - eight patients presenting with CAKUT carrying an 1q23.3q24.1 microdeletion. They defined a 276-kb minimal common region that only overlaps with the PBX1 gene. 5 patients presented with varying degrees of hearing impairment (no detailed assessments). Patient 8, in which the deletion only covers the PBX1 gene showed an obvious bilateral dysplasia leading to a conductive hearing defect.
Early onset dystonia v1.99 GAMT Eldar Dedic reviewed gene: GAMT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19027335, 33996490, 12557293, 19288536, 16855203; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.53 PBX1 Eleanor Williams Deleted their review
DDG2P v2.53 PBX1 Eleanor Williams Deleted their comment
DDG2P v2.53 PBX1 Eleanor Williams commented on gene: PBX1
Monogenic hearing loss v2.212 PBX1 Eleanor Williams Classified gene: PBX1 as Amber List (moderate evidence)
Monogenic hearing loss v2.212 PBX1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 3 cases but in 1 case 7 other genes also deleted, and in another hearing loss was unilateral only.
Monogenic hearing loss v2.212 PBX1 Eleanor Williams Gene: pbx1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.211 PBX1 Eleanor Williams Phenotypes for gene: PBX1 were changed from Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay to Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, OMIM:617641; congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, MONDO:0060549
Monogenic hearing loss v2.210 PBX1 Eleanor Williams Publications for gene: PBX1 were set to
Monogenic hearing loss v2.209 PBX1 Eleanor Williams reviewed gene: PBX1: Rating: ; Mode of pathogenicity: None; Publications: 28566479, 29036646; Phenotypes: Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, OMIM:617641; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.478 BET1 Dmitrijs Rots gene: BET1 was added
gene: BET1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: BET1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BET1 were set to PMID: 34779586
Phenotypes for gene: BET1 were set to Epilepsy; congenical musculara dystrophy
Penetrance for gene: BET1 were set to Complete
Review for gene: BET1 was set to GREEN
Added comment: 3 reported individuals from two families with biallelic variants and functional data supporting the role of the variants in the phenotype. Enough evidence for green rating.
Sources: Literature
Congenital muscular dystrophy v2.21 BET1 Dmitrijs Rots reviewed gene: BET1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34779586; Phenotypes: Congenital muscular dystrophy, epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary ovarian insufficiency v1.61 POLR3H Ivone Leong Tag watchlist tag was added to gene: POLR3H.
Primary ovarian insufficiency v1.61 POLR3H Ivone Leong Classified gene: POLR3H as Amber List (moderate evidence)
Primary ovarian insufficiency v1.61 POLR3H Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in Gene2Phenotype and it is not present in OMIM. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Primary ovarian insufficiency v1.61 POLR3H Ivone Leong Gene: polr3h has been classified as Amber List (Moderate Evidence).
Cardiac arrhythmias - additional genes v1.14 GNB5 Arina Puzriakova Classified gene: GNB5 as Amber List (moderate evidence)
Cardiac arrhythmias - additional genes v1.14 GNB5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. >3 unrelated families with cardiac arrhythmia identified, which may be the main presenting feature. This also may be the most likely route for testing in some cases, particularly where no seizures and only mild cognitive impairment are observed.
Cardiac arrhythmias - additional genes v1.14 GNB5 Arina Puzriakova Gene: gnb5 has been classified as Amber List (Moderate Evidence).
Corneal dystrophy v1.8 TCF4 Ivone Leong Phenotypes for gene: TCF4 were changed from Corneal dystrophy, Fuchs endothelial, 3, 613267 to Corneal dystrophy, Fuchs endothelial, 3, OMIM:613267
Optic neuropathy v2.54 ALPK1 Ivone Leong Phenotypes for gene: ALPK1 were changed from Retinopathy; Optic disc swelling; Splenomegaly; Pancytopenia; Headaches; ocular inflammation. to ROSAH syndrome, OMIM:614979
Optic neuropathy v2.53 ALPK1 Ivone Leong Classified gene: ALPK1 as Amber List (moderate evidence)
Optic neuropathy v2.53 ALPK1 Ivone Leong Added comment: Comment on list classification: New gene added by Neringa Jurkute (MD). This gene is associated with a phenotype in OMIM and Gene2Phenotype (Strong). There is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
Optic neuropathy v2.53 ALPK1 Ivone Leong Gene: alpk1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.52 ALPK1 Ivone Leong Tag Q4_21_rating tag was added to gene: ALPK1.
Tag Q4_21_NHS_review tag was added to gene: ALPK1.
Optic neuropathy v2.52 ALPK1 Ivone Leong Publications for gene: ALPK1 were set to PMID: 30967659; 31053777; 31939038; 34159509
Retinal disorders v2.239 ALPK1 Ivone Leong Tag Q4_21_NHS_review tag was added to gene: ALPK1.
Retinal disorders v2.239 ALPK1 Ivone Leong Added comment: Comment on publications: Added new publication (PMID:31053777;34159509).
Retinal disorders v2.239 ALPK1 Ivone Leong Publications for gene: ALPK1 were set to 30967659; 31939038
Retinal disorders v2.238 HKDC1 Ivone Leong Classified gene: HKDC1 as Red List (low evidence)
Retinal disorders v2.238 HKDC1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (limited). PMID: 30085091 also describes a mouse knockout model. In the mouse model, the retinal degeneration phenotypes were mild (like that seen in humans) and did not have retinal phenotypes until 9 months (similar to the late onset in humans). There is currently not enough evidence to support a gene-disease association. This gene is borderline Red/Amber.
Retinal disorders v2.238 HKDC1 Ivone Leong Gene: hkdc1 has been classified as Red List (Low Evidence).
Cardiac arrhythmias - additional genes v1.13 GNB5 Arina Puzriakova gene: GNB5 was added
gene: GNB5 was added to Cardiac arrhythmias - additional genes. Sources: Literature
Q4_21_rating tags were added to gene: GNB5.
Mode of inheritance for gene: GNB5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNB5 were set to 27523599; 28697420; 29368331; 33172956
Phenotypes for gene: GNB5 were set to Intellectual developmental disorder with cardiac arrhythmia, OMIM:617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, OMIM:617182
Review for gene: GNB5 was set to GREEN
Added comment: Biallelic GNB5 pathogenic variants cause two relevant phenotypes: intellectual developmental disorder with cardiac arrhythmia (MIM 617173) or language delay and ADHD/cognitive impairment with or without cardiac arrhythmia (MIM 617182).

Heart rate disturbances (in most cases reminiscent of sick sinus syndrome) have been reported as a feature of both disorders. At least 8 unrelated families with arrhythmias associated with variants in this gene reported in literature. Cardiac involvement supported by animal model studies.
Sources: Literature
Retinal disorders v2.237 HKDC1 Ivone Leong Phenotypes for gene: HKDC1 were changed from Retinitis pigmentosa 92, MIM# 619614 to Retinitis pigmentosa 92, OMIM:619614
Intellectual disability v3.1479 GNB5 Arina Puzriakova Phenotypes for gene: GNB5 were changed from Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; Intellectual developmental disorder with cardiac arrhythmia, 617173 to Intellectual developmental disorder with cardiac arrhythmia, OMIM:617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, OMIM:617182
Early onset or syndromic epilepsy v2.478 GNB5 Arina Puzriakova Phenotypes for gene: GNB5 were changed from Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; early infantile epileptic encephalopathy (EIEE) to Intellectual developmental disorder with cardiac arrhythmia, OMIM:617173
Early onset dystonia v1.99 FOXG1 Eldar Dedic changed review comment from: Dzinovic, et al. (2021, PMID: 34399161) analyzed 45 pediatric complex dystonia cases. The whole-exome-sequencing revealed de novo heterozygous FOXG1 c.703C >T (p.Leu235Phe) variant in 3 years of age female case of European ethnicity. Parents were Sanger sequenced.

- Please note that FOXG1 c.703C >T (p.Leu235Phe) variant was absent from gnomAD v2.1.1 as of December 2021

Wong, et al. (2019, PMID: 31316448) analyzed 30 cases with encephalopathy and movement impairments. Whole-exome-sequencing revealed 3 variants (c.763 T>C (p.Trp255Arg); c.250delC (p.Gln86Argfs*106); c.256dupC (p.Gln86Aspfs*34)) in FOXG1 gene in 3 Han Chinese cases (between 2 and 17 years of age) from Taiwan who had dystonia , respectively (Table 1).

- Please note that FOXG1 c.250delC (p.Gln86Argfs*106) variant was filtered from gnomAD v2.1.1, while FOXG1 c.763 T>C (p.Trp255Arg) and FOXG1 c.256dupC (p.Gln86Aspfs*34) variants were absent from gnomAD v2.1.1 as of December 2021

Mencarelli, et al. (2010, PMID: 19578037) analyzed 107 cases of European origin (including 60 Rett syndrome (RTT), 43 encephalopathy, and 4 RTT-like patients). The FOXG1 c.643T>C (p.Phe215Leu) variant has been found de novo in one 8 years of age female RTT patient with dystonia (diagnosed at 2 years of age) of French origin.

- Please note that FOXG1 c.643T>C (p.Phe215Leu) variant was absent from gnomAD v2.1.1 as of December 2021; to: Dzinovic, et al. (2021, PMID: 34399161) analyzed 45 pediatric complex dystonia cases. The whole-exome-sequencing revealed de novo heterozygous FOXG1 c.703C >T (p.Leu235Phe) variant in 3 years of age female case of European ethnicity. Parents were Sanger sequenced.

- Please note that FOXG1 c.703C >T (p.Leu235Phe) variant was absent from gnomAD v2.1.1 as of December 2021

Wong, et al. (2019, PMID: 31316448) analyzed 30 cases with encephalopathy and movement impairments. Whole-exome-sequencing revealed 3 variants (c.763 T>C (p.Trp255Arg); c.250delC (p.Gln86Argfs*106); c.256dupC (p.Gln86Aspfs*34)) in FOXG1 gene in 3 Han Chinese cases (between 2 and 17 years of age) from Taiwan who had dystonia, respectively (Table 1).

- Please note that FOXG1 c.250delC (p.Gln86Argfs*106) variant was filtered from gnomAD v2.1.1, while FOXG1 c.763 T>C (p.Trp255Arg) and FOXG1 c.256dupC (p.Gln86Aspfs*34) variants were absent from gnomAD v2.1.1 as of December 2021

Mencarelli, et al. (2010, PMID: 19578037) analyzed 107 cases of European origin (including 60 Rett syndrome (RTT), 43 encephalopathy, and 4 RTT-like patients). The FOXG1 c.643T>C (p.Phe215Leu) variant has been found de novo in one 8 years of age female RTT patient with dystonia (diagnosed at 2 years of age) of French origin.

- Please note that FOXG1 c.643T>C (p.Phe215Leu) variant was absent from gnomAD v2.1.1 as of December 2021
Early onset dystonia v1.99 FOXG1 Eldar Dedic reviewed gene: FOXG1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34399161, 31316448, 19578037; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.112 NPRL2 Ivone Leong Penetrance for gene NPRL2 was set from to None
Malformations of cortical development v2.111 NPRL2 Ivone Leong Classified gene: NPRL2 as Amber List (moderate evidence)
Malformations of cortical development v2.111 NPRL2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. It should be noted that not all patients with variants in this gene has focal cortical dysplasia; however, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Malformations of cortical development v2.111 NPRL2 Ivone Leong Gene: nprl2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.110 NPRL2 Ivone Leong Tag Q4_21_rating tag was added to gene: NPRL2.
Malformations of cortical development v2.110 NPRL2 Ivone Leong Added comment: Comment on publications: PMID: 30093711 describes another 2 cases with FCD.
Malformations of cortical development v2.110 NPRL2 Ivone Leong Publications for gene: NPRL2 were set to 29281825; 27173016; 31625153
Optic neuropathy v2.51 ALPK1 Neringa Jurkute changed review comment from: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individual shared overlapping phenotype with retinal dystrophy, chronic disc swelling observed in majority of cases.
Sources: Literature, Research, Other; to: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individuals shared overlapping phenotype with retinal changes, chronic disc swelling observed in majority of cases.

OMIM: 614979
PMID: 30967659; 31053777; 31939038; 34159509
Sources: Literature, Research, Other
Retinal disorders v2.236 ALPK1 Neringa Jurkute changed review comment from: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individuals shared overlapping phenotype with retinal dystrophy, chronic disc swelling observed in majority of cases.

PMID: 30967659; 31053777; 31939038; 34159509; to: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individuals shared overlapping phenotype with retinal changes, chronic disc swelling observed in majority of cases.

OMIM: 614979

PMID: 30967659; 31053777; 31939038; 34159509
Retinal disorders v2.236 ALPK1 Neringa Jurkute changed review comment from: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individual shared overlapping phenotype with retinal dystrophy, chronic disc swelling observed in majority of cases.

PMID: 30967659; 31053777; 31939038; 34159509; to: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individuals shared overlapping phenotype with retinal dystrophy, chronic disc swelling observed in majority of cases.

PMID: 30967659; 31053777; 31939038; 34159509
Retinal disorders v2.236 ALPK1 Neringa Jurkute reviewed gene: ALPK1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30967659, 31053777, 31939038, 34159509; Phenotypes: Retinal dystrophy, optic disc swelling, splenomegaly, headaches, ocular inflammation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.109 NPRL2 Ivone Leong Phenotypes for gene: NPRL2 were changed from Epilepsy, familial focal, with variable foci 2, MIM# 617116 to Epilepsy, familial focal, with variable foci 2, OMIM:617116
Optic neuropathy v2.51 ALPK1 Neringa Jurkute changed review comment from: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individual shared overlapping phenotype with retinal dystrophy, chronic disc swelling observed in majority of cases.
Sources: Literature, Research, Other; to: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individual shared overlapping phenotype with retinal dystrophy, chronic disc swelling observed in majority of cases.
Sources: Literature, Research, Other
Optic neuropathy v2.51 ALPK1 Neringa Jurkute gene: ALPK1 was added
gene: ALPK1 was added to Optic neuropathy. Sources: Literature,Research,Other
Mode of inheritance for gene: ALPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALPK1 were set to PMID: 30967659; 31053777; 31939038; 34159509
Phenotypes for gene: ALPK1 were set to Retinopathy; Optic disc swelling; Splenomegaly; Pancytopenia; Headaches; ocular inflammation.
Mode of pathogenicity for gene: ALPK1 was set to Other
Review for gene: ALPK1 was set to GREEN
Added comment: Recurrent variant has been reported in affected individuals from 9 unrelated families. Affected individual shared overlapping phenotype with retinal dystrophy, chronic disc swelling observed in majority of cases.
Sources: Literature, Research, Other
Malformations of cortical development v2.108 GRIN2B Ivone Leong Classified gene: GRIN2B as Amber List (moderate evidence)
Malformations of cortical development v2.108 GRIN2B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Malformations of cortical development v2.108 GRIN2B Ivone Leong Gene: grin2b has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.107 GRIN2B Ivone Leong Tag Q4_21_rating tag was added to gene: GRIN2B.
Malformations of cortical development v2.107 GRIN2B Ivone Leong Phenotypes for gene: GRIN2B were changed from Mental retardation, autosomal dominant 6, MIM# 613970 to Intellectual developmental disorder, autosomal dominant 6, with or without seizures, OMIM:613970
Malformations of cortical development v2.106 SCN3A Ivone Leong Classified gene: SCN3A as Amber List (moderate evidence)
Malformations of cortical development v2.106 SCN3A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (Strong). PMID: 34081427 reports that 31/38 (82%) cases have malformation of cortical development. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Malformations of cortical development v2.106 SCN3A Ivone Leong Gene: scn3a has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.105 SCN3A Ivone Leong Tag Q4_21_rating tag was added to gene: SCN3A.
Malformations of cortical development v2.105 SCN3A Ivone Leong Publications for gene: SCN3A were set to 32515017; 30146301
Malformations of cortical development v2.104 SCN3A Ivone Leong Phenotypes for gene: SCN3A were changed from Polymicrogyria; malformations of cortical development; epilepsy to Polymicrogyria, MONDO:0000087; malformations of cortical development; epilepsy, MONDO:0005027; Developmental and epileptic encephalopathy 62, OMIM:617938
Malformations of cortical development v2.103 ATP1A3 Ivone Leong Phenotypes for gene: ATP1A3 were changed from Polymicrogyria; epilepsy; developmental delay to Polymicrogyria, MONDO:0000087; epilepsy, MONDO:0005027; developmental delay; Developmental and epileptic encephalopathy 99, OMIM:619606
Malformations of cortical development v2.102 ATP1A3 Ivone Leong Classified gene: ATP1A3 as Amber List (moderate evidence)
Malformations of cortical development v2.102 ATP1A3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. PMID:33880529 describes additional cases of patients with variants in ATP1A3 who have polymicrogyria. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Malformations of cortical development v2.102 ATP1A3 Ivone Leong Gene: atp1a3 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.101 ATP1A3 Ivone Leong Publications for gene: ATP1A3 were set to 33762331
Malformations of cortical development v2.100 ATP1A3 Ivone Leong Tag Q4_21_rating tag was added to gene: ATP1A3.
Familial dysautonomia v1.15 PHOX2B Arina Puzriakova Tag currently-ngs-unreportable was removed from gene: PHOX2B.
Early onset dystonia v1.99 ARX Eldar Dedic reviewed gene: ARX: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31324350, 29778428, 23657928, 29343471; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset dystonia v1.99 ACTB Eldar Dedic reviewed gene: ACTB: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 31970217, 29788902, 28849312, 27862284, 29220674, 25255767; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset dystonia v1.99 ACTB Eldar Dedic Deleted their review
Early onset dystonia v1.99 ACTB Eldar Dedic Deleted their comment
Early onset dystonia v1.99 AFG3L2 Eldar Dedic reviewed gene: AFG3L2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 32219868; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Brain channelopathy v1.70 CACNA1A Zornitza Stark changed review comment from: Four infants, all presenting with hypotonia, mild facial dysmorphic features, encephalopathy, and seizures, born
to consanguineous parents. Testing was only performed on two of the newborns in the family. A novel homozygous nonsense c.2767C>T p.(Arg932*) variant in the exon 19 of the CACNA1A gene (NM_001127221.1). Segregation analysis showed that both parents were heterozygous carriers and they were diagnosed with EA2.; to: Four infants, all presenting with hypotonia, mild facial dysmorphic features, encephalopathy, and seizures, born
to consanguineous parents. Testing was only performed on two of the newborns in the family. A novel homozygous nonsense c.2767C>T p.(Arg932*) variant in the exon 19 of the CACNA1A gene (NM_001127221.1). Segregation analysis showed that both parents were heterozygous carriers and they were diagnosed with EA2.

Well established association between mono-allelic variants and a number of phenotypes including episodic ataxia.
Brain channelopathy v1.70 CACNA1A Zornitza Stark reviewed gene: CACNA1A: Rating: RED; Mode of pathogenicity: None; Publications: 34267336; Phenotypes: Hypotonia, encephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.68 MLIP Zornitza Stark gene: MLIP was added
gene: MLIP was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene: MLIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MLIP were set to 34581780
Phenotypes for gene: MLIP were set to MLIP-related myopathy with rhabdomyolysis
Review for gene: MLIP was set to GREEN
Added comment: PMID: 34581780: 7 individuals with 6 families with truncating (one splice that also resulted in a frameshift variant) biallelic variants (used NM_1281746).

In 3 patients patients’ skeletal muscle, these variants were shown to cause reduction overall RNA expression levels of the predominant MLIP isoform.

Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels.
Sources: Literature
Congenital disorders of glycosylation v2.78 STT3A Zornitza Stark changed review comment from: Three families reported to date.; to: Bi-allelic variants: Three families reported to date.
Congenital disorders of glycosylation v2.78 STT3A Zornitza Stark edited their review of gene: STT3A: Added comment: New MOI

PMID: 34653363 - 16 patients from 9 families with new AD mode of inheritance (both de novo and inherited). All variants were missense within/around acritical active/catalytic sites. Patients aged 3-55yo, with children noted to be "healthy" until reaching young adulthood
Clinical features include dysmorphic features, macrocephaly (6/16), mild-moderate ID/DD (10/16), short stature (8/16), skeletal abnormalities (10/16), muscle cramps (7/16).
Functional studies verifies AR disease is caused by LOF variants, whereas the AD variants cause DN proven by cotransfection in WT yeast resulting in impaired glycosylation (protein levels unchanged).; Changed publications to: 23842455, 30701557, 28424003, 34653363; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.63 KIAA0391 Zornitza Stark gene: KIAA0391 was added
gene: KIAA0391 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: KIAA0391 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0391 were set to 34715011
Phenotypes for gene: KIAA0391 were set to Hearing loss, intellectual disability
Review for gene: KIAA0391 was set to GREEN
gene: KIAA0391 was marked as current diagnostic
Added comment: Four unrelated families with multisystem disease associated with bi-allelic variants in PRORP, HGNC approved name is KIAA0391. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes.

-1 consanguineous family with homozygous missense in 3 affected sisters, het parents unaffected. Siblings had profound bilateral SNHL in infancy. In teens developed primary amenorrhea/Perrault syndrome, and hypergonadotropic hypogonadism.
-1 unrelated male with compound het missense, each inherited from an unaffected parent. Hearing loss noted at 3, diagnosed at 5.
-1 unrelated male compound het for a missense and a frameshift. appendicular hypertonia in infancy, mild dysmorphism. Severe global dev delay at 20 months. Normal hearing at 18 months, but at 3 years had bilateral SNHL.
-an affected mother and her 2 affected children (son and daughter), homozygous for a missense. Father is heterozygous and unaffected. Son has psychotic disorder, autistic traits. Sister had intrauterine growth retardation, global developmental delay, and seizures in the first years of life. Mother presented with retrobulbar optic neuritis and tonic pupil at 39 years of age, then with asthenia, myalgias, memory loss, and frequent headaches.
Sources: Literature
Congenital disorders of glycosylation v2.78 OSTC Zornitza Stark gene: OSTC was added
gene: OSTC was added to Congenital disorders of glycosylation. Sources: Literature
Mode of inheritance for gene: OSTC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSTC were set to 32267060
Phenotypes for gene: OSTC were set to Oligosaccharyltransferase complex-congenital disorders of glycosylation
Review for gene: OSTC was set to RED
Added comment: A patient with microcephaly, dysmorphic facies, congenital heart defect, focal epilepsy, infantile spasms, skeletal dysplasia, and a type 1 serum transferrin isoelectrofocusing due to a novel CDG caused by a homozygous variant in the oligosaccharyltransferase complex noncatalytic subunit (OSTC) gene involved in glycosylation and confirmed by serum transferrin electrophoresis.
Patient was homozygous for a canonical splice variant (c.431 + 1G > A), mRNA from patient's fibroblast showed mRNA transcript reduced 80-90%/aberrant splicing - predicting NMD.
GnomAD - 10 hets, 0 hom
Sources: Literature
Early onset or syndromic epilepsy v2.477 KCNC2 Zornitza Stark gene: KCNC2 was added
gene: KCNC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KCNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNC2 were set to 32392612; 31972370
Phenotypes for gene: KCNC2 were set to epileptic encephalopathy; spastic tetraplegia; opisthotonus attacks; intellectual disability; West syndrome
Review for gene: KCNC2 was set to AMBER
Added comment: PMID: 31972370. De novo missense variant (p.Val471Leu) identified in a child with early severe developmental and epileptic encephalopathy, spastic tetraplegia, opisthotonos attacks.

PMID: 32392612. De novo missense variant (p.Asp167Tyr) identified in a neurofibromatosis type 1 related West syndrome patient. Functional analysis showed a significant reduction of the mean potassium current and a shift in the voltage dependence of steady-state activation. Maternally inherited NF1 variant (p.T1951Nfs*5) also identified, the mother was "clinically unremarkable".
Sources: Literature
Intellectual disability v3.1478 NSRP1 Zornitza Stark gene: NSRP1 was added
gene: NSRP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to Epilepsy; Cerebral palsy; microcephaly; Intellectual disability
Review for gene: NSRP1 was set to GREEN
gene: NSRP1 was marked as current diagnostic
Added comment: Novel gene regulating splicing. Biallelic LoF pathogenic variants reported in 6 individuals from 3 unrelated families associated with a phenotype characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.
Sources: Literature
Intellectual disability v3.1478 SPRED2 Zornitza Stark gene: SPRED2 was added
gene: SPRED2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPRED2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRED2 were set to 34626534
Phenotypes for gene: SPRED2 were set to developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt
Review for gene: SPRED2 was set to GREEN
gene: SPRED2 was marked as current diagnostic
Added comment: PMID: 34626534
Homozygosity for three different variants c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95) were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behaviour. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome.
Sources: Literature
Intellectual disability v3.1478 SPATA5L1 Zornitza Stark gene: SPATA5L1 was added
gene: SPATA5L1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPATA5L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA5L1 were set to 34626583
Phenotypes for gene: SPATA5L1 were set to Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616
Review for gene: SPATA5L1 was set to GREEN
gene: SPATA5L1 was marked as current diagnostic
Added comment: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly.

~53% of patients had ID.
Sources: Literature
Mitochondrial disorders v2.63 TARS2 Zornitza Stark reviewed gene: TARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33153448, 24827421, 34508595; Phenotypes: Combined oxidative phosphorylation deficiency 21 - 615918; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1478 OGDHL Zornitza Stark gene: OGDHL was added
gene: OGDHL was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to 34800363
Phenotypes for gene: OGDHL were set to Neurodevelopmental disorder featuring epilepsy, hearing loss and visual impairment
Review for gene: OGDHL was set to GREEN
Added comment: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Sources: Literature
Mitochondrial disorders v2.63 OGDH Zornitza Stark reviewed gene: OGDH: Rating: AMBER; Mode of pathogenicity: None; Publications: 32383294; Phenotypes: Developmental delay, ataxia, seizure, raised lactate; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.501 HIBADH Zornitza Stark gene: HIBADH was added
gene: HIBADH was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: HIBADH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIBADH were set to 34176136
Phenotypes for gene: HIBADH were set to organic aciduria
Review for gene: HIBADH was set to RED
Added comment: Single family reported with two siblings presenting with 3-Hydroxyisobutyric aciduria. Male sib with neurodevelopmental symptoms, female sibling asymptomatic. No functional studies
Sources: Literature
Severe microcephaly v2.274 ARPC4 Zornitza Stark gene: ARPC4 was added
gene: ARPC4 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: ARPC4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARPC4 were set to DOI:https://doi.org/10.1016/j.xhgg.2021.100072
Phenotypes for gene: ARPC4 were set to Microcephaly; mild motor delays; significant speech impairment
Review for gene: ARPC4 was set to GREEN
Added comment: 7 affected individuals from 6 families (gonadal mosaicism was confirmed in the mother of the 2 affected siblings) with a recurrent missense variant (NM_005718.4:c.472C>T; p.R158C). 6/7 affected individuals had microcephaly. The variant was associated with a decreased amount of F-actin in cells from two affected individuals.
Sources: Literature
Adult onset leukodystrophy v1.36 LAMB1 Zornitza Stark changed review comment from: Mono-allelic LAMB1 variants reported in 5 families with cerebral small vessel disease. 4 are truncating frameshifts (and 2 of the families have the same frameshift), 1 is a canonical splice. All families had adult onset of symptoms ranging from 20-63yo. All has white matter hyper intensity on imaging.; to: New MOI

Mono-allelic LAMB1 variants reported in 5 families with cerebral small vessel disease. 4 are truncating frameshifts (and 2 of the families have the same frameshift), 1 is a canonical splice. All families had adult onset of symptoms ranging from 20-63yo. All has white matter hyper intensity on imaging.
Adult onset leukodystrophy v1.36 LAMB1 Zornitza Stark edited their review of gene: LAMB1: Added comment: Mono-allelic LAMB1 variants reported in 5 families with cerebral small vessel disease. 4 are truncating frameshifts (and 2 of the families have the same frameshift), 1 is a canonical splice. All families had adult onset of symptoms ranging from 20-63yo. All has white matter hyper intensity on imaging.; Changed rating: GREEN; Changed publications to: 32548278, 34606115; Changed phenotypes to: Adult-onset leukodystrophy; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1478 FOXR1 Zornitza Stark gene: FOXR1 was added
gene: FOXR1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FOXR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXR1 were set to 34723967
Phenotypes for gene: FOXR1 were set to Postnatal microcephaly, progressive brain atrophy and global developmental delay
Review for gene: FOXR1 was set to AMBER
Added comment: 1 patient described with a de novo missense variant. Phenotypes include: postnatal microcephaly, progressive brain atrophy, skeletal abnormalities, brain abnormalities, ophthalmic abnormalities, neuromuscular abnormalities, and dysmorphic features. A variant in ATP1A3 was considered to have contributed to the final phenotype.

In vitro functional evidence is supportive of pathogenicity (variant causes protein instability and abnormal nuclear aggregation).

A mouse knockout has comparable phenotypes, and a severe survival deficit.

Rated amber (1 patient, functional evidence, mouse model).
Sources: Literature
Possible mitochondrial disorder - nuclear genes v1.60 SLIRP Zornitza Stark gene: SLIRP was added
gene: SLIRP was added to Possible mitochondrial disorder - nuclear genes. Sources: Literature
Mode of inheritance for gene: SLIRP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLIRP were set to 34426662
Phenotypes for gene: SLIRP were set to Mitochondrial encephalomyopathy with complex I and IV deficiency
Review for gene: SLIRP was set to RED
Added comment: Single Dutch non-consanguineous patient having mitochondrial encephalomyopathy with complex I and complex IV deficiency, whole exome sequencing revealed two compound heterozygous variants (NM_031210.5:c.248_252del; NP_112487.1:p.(Ile83Argfs*10) and NC_000014.8:g.78177003 A > G; NM_031210.5:c.98-178 A > G) in SLIRP. Report SLIRP variants as a novel cause of mitochondrial encephalomyopathy with OXPHOS deficiency
Sources: Literature
Possible mitochondrial disorder - nuclear genes v1.60 ATP5A1 Zornitza Stark reviewed gene: ATP5A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34483339; Phenotypes: feeding intolerance, failure to thrive, hyperammonaemia, lactic acidaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.819 TAB2 Zornitza Stark reviewed gene: TAB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34456334; Phenotypes: Mitral valve disease, cardiomyopathy, short stature and hypermobility, Rasopathy-like; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.498 CARD10 Zornitza Stark gene: CARD10 was added
gene: CARD10 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CARD10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CARD10 were set to 32238915
Phenotypes for gene: CARD10 were set to Immunodeficiency 89 and autoimmunity, MIM# 619632
Review for gene: CARD10 was set to RED
Added comment: A pair of siblings reported with adult onset of recurrent infections, allergies, microcytic anaemia, and Crohn disease. Homozygous missense variant.
Sources: Literature
Primary ovarian insufficiency v1.60 POLR3H Zornitza Stark gene: POLR3H was added
gene: POLR3H was added to Primary ovarian insufficiency. Sources: Expert Review
Mode of inheritance for gene: POLR3H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3H were set to 34794894; 30830215
Phenotypes for gene: POLR3H were set to Primary ovarian insufficiency
Review for gene: POLR3H was set to AMBER
Added comment: A homozygous missense variant (p.Asp50Gly) was identified homozygous in 2 unrelated families. A mull mouse model was embryonic lethal, but a mouse model homozygous for the missense were viable and showed delayed pubertal development, characterised by late first oestrus or preputial separation.
Sources: Expert Review
Primary ovarian insufficiency v1.60 POLR2C Zornitza Stark gene: POLR2C was added
gene: POLR2C was added to Primary ovarian insufficiency. Sources: Literature
Mode of inheritance for gene: POLR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR2C were set to 34794894; 29367954
Phenotypes for gene: POLR2C were set to Primary ovarian insufficiency
Review for gene: POLR2C was set to AMBER
Added comment: One family with POI segregating a nonsense variant (p.Lys152Ter) and a case with sporadic POI with a splice region variant (c.206-3C>T). Knockdown of the gene in an embryonic carcinoma cell line resulted in decreased protein production and impaired cell proliferation.
Two missense in premature ovarian failure cases submitted to ClinVar by Shandong Provincial Hospital Affiliated to Shandong University (SCV001877131.1, SCV001877153.1).
Sources: Literature
Primary ovarian insufficiency v1.60 KHDRBS1 Zornitza Stark gene: KHDRBS1 was added
gene: KHDRBS1 was added to Primary ovarian insufficiency. Sources: Literature
Mode of inheritance for gene: KHDRBS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KHDRBS1 were set to 34794894; 29808484; 28938739; 20881015
Phenotypes for gene: KHDRBS1 were set to Premature ovarian failure
Review for gene: KHDRBS1 was set to GREEN
gene: KHDRBS1 was marked as current diagnostic
Added comment: 4 individuals in 3 unrelated families and a supporting mouse model
PMID: 28938739 - missense (c.460A > G, p.M154V) identified in a Chinese mother and daughter with POI, and another missense (c.263C > T, p.P88L) identified in an idiopathic POI case.
SCV001364312.1 - case with POI and missense (p.Pro421Leu) submitted by an Italian institute (ClinVar ID: 929733)
PMID: 29808484 - missense (p.Pro296Leu) identified in a POI case, which also has a heterozygous missense in FGFR2. There are 12 hets with Pro296Leu in gnomAD v2.1. This case is not included in the final case count.
PMID: 20881015 - supporting null mouse model. Female mice were subfertile.
Sources: Literature
Retinal disorders v2.236 HKDC1 Zornitza Stark gene: HKDC1 was added
gene: HKDC1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: HKDC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HKDC1 were set to 30085091
Phenotypes for gene: HKDC1 were set to Retinitis pigmentosa 92, MIM# 619614
Review for gene: HKDC1 was set to RED
Added comment: Two unrelated Chinese men reported with relatively late-onset RP, and same homozygous missense variant.
Sources: Literature
Congenital hyperinsulinism v2.8 NSD1 Ivone Leong Tag Q4_21_rating tag was added to gene: NSD1.
Congenital hyperinsulinism v2.8 NSD1 Ivone Leong Classified gene: NSD1 as Amber List (moderate evidence)
Congenital hyperinsulinism v2.8 NSD1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (Definitive). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Congenital hyperinsulinism v2.8 NSD1 Ivone Leong Gene: nsd1 has been classified as Amber List (Moderate Evidence).
Congenital hyperinsulinism v2.7 GPC3 Ivone Leong Tag Q4_21_phenotype tag was added to gene: GPC3.
Congenital hyperinsulinism v2.7 AKT2 Ivone Leong Tag Q4_21_phenotype tag was added to gene: AKT2.
Congenital hyperinsulinism v2.7 AKT2 Ivone Leong Tag Q4_21_expert_review tag was added to gene: AKT2.
Congenital hyperinsulinism v2.7 GPC3 Ivone Leong Tag Q4_21_expert_review tag was added to gene: GPC3.
Congenital hyperinsulinism v2.7 UCP2 Ivone Leong Tag watchlist tag was added to gene: UCP2.
Congenital hyperinsulinism v2.7 UCP2 Ivone Leong Classified gene: UCP2 as Amber List (moderate evidence)
Congenital hyperinsulinism v2.7 UCP2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Congenital hyperinsulinism v2.7 UCP2 Ivone Leong Gene: ucp2 has been classified as Amber List (Moderate Evidence).
Congenital hyperinsulinism v2.6 UCP2 Ivone Leong Phenotypes for gene: UCP2 were changed from Hyperinsulinism to Hyperinsulinism, MONDO:0002177
Pituitary hormone deficiency v2.10 RNPC3 Ivone Leong Classified gene: RNPC3 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.10 RNPC3 Ivone Leong Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.9 RNPC3 Ivone Leong Tag watchlist tag was added to gene: RNPC3.
Pituitary hormone deficiency v2.9 RNPC3 Ivone Leong edited their review of gene: RNPC3: Added comment: PMID:33650182 a third case reported with growth failure, second case with ID and growth failure. In this case the patient has GH and PRL deficiencies, as well as undetectably low IGF1 levels. This is the second case where there are >2 pituitary hormone deficiency. Thefore this gene should be promoted from Red to Amber.; Changed rating: AMBER; Changed publications to: 33650182
Intellectual disability v3.1478 RNPC3 Ivone Leong changed review comment from: PMID:33650182 a third case reported with growth failure and ID. This is the second case where a patient with a variant in RNPC3 has ID. Therefore the Amber rating.; to: PMID:33650182 a third case reported with growth failure. This is the second case where a patient with a variant in RNPC3 has ID. Therefore the Amber rating.
Intellectual disability v3.1478 RNPC3 Ivone Leong changed review comment from: PMID:33650182 a third case reported with growth failure and ID.; to: PMID:33650182 a third case reported with growth failure and ID. This is the second case where a patient with a variant in RNPC3 has ID. Therefore the Amber rating.
Intellectual disability v3.1478 RNPC3 Ivone Leong changed review comment from: Comment on list classification: Promoted from Red to Amber based on my other review.; to: Comment on list classification: Promoted from Red to Amber based on my other review.
Pituitary hormone deficiency v2.9 RNPC3 Ivone Leong Phenotypes for gene: RNPC3 were changed from isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160 to Pituitary hormone deficiency, combined or isolated, 7, OMIM:618160
Pituitary hormone deficiency v2.8 RNPC3 Ivone Leong Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
Intellectual disability v3.1478 RNPC3 Ivone Leong Tag watchlist tag was added to gene: RNPC3.
IUGR and IGF abnormalities v1.49 RNPC3 Ivone Leong Classified gene: RNPC3 as Green List (high evidence)
IUGR and IGF abnormalities v1.49 RNPC3 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. PMID:33650182 a third case reported with growth failure and ID. There is now enough evidence to support a gene-disease association.
IUGR and IGF abnormalities v1.49 RNPC3 Ivone Leong Gene: rnpc3 has been classified as Green List (High Evidence).
IUGR and IGF abnormalities v1.48 RNPC3 Ivone Leong Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
IUGR and IGF abnormalities v1.47 RNPC3 Ivone Leong Phenotypes for gene: RNPC3 were changed from isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160 to Pituitary hormone deficiency, combined or isolated, 7, OMIM:618160
Intellectual disability v3.1478 RNPC3 Ivone Leong Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
Intellectual disability v3.1477 RNPC3 Ivone Leong Phenotypes for gene: RNPC3 were changed from isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160; developmental delay/intellectual deficiency and delayed puberty to Pituitary hormone deficiency, combined or isolated, 7, OMIM:618160
Intellectual disability v3.1476 RNPC3 Ivone Leong Classified gene: RNPC3 as Amber List (moderate evidence)
Intellectual disability v3.1476 RNPC3 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on my other review.
Intellectual disability v3.1476 RNPC3 Ivone Leong Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1475 RNPC3 Ivone Leong edited their review of gene: RNPC3: Added comment: PMID:33650182 a third case reported with growth failure and ID.; Changed rating: AMBER; Changed publications to: 24480542, 29866761, 32462814, 33650182
Early onset dystonia v1.99 ACTB Eldar Dedic changed review comment from: Freitas, et al. (2020, PMID 31970217) presented 52 years of age Brazilian female case with dystonia (onset at age of 25 years) who had additional clinical features (but without facial dysmorphism and brain abnormalities). Whole-exome-sequencing showed the presence of ACTB c.547C>T (p.Arg183Trp) variant. This variant was absent from gnomAD v2.1.1 as of December 2021.

Skogseid, et al. (2018, PMID 29788902) presented 23 years old female case with dystonia (age at onset 13 years), mild dysmorphic facial traits and additional clinical features (but with grossly maintained brain structure). Whole-exome-sequencing revealed heterozygous ACTB c.547C>T (p.Arg183Trp) variant. The case was negative for the aCGH analysis.

Zech, et al. (2017, PMID 28849312) presented 9 unrelated cases with combined and/or complex dystonia (8 of European and 1 of Asian origin). Whole-exome-sequencing revealed de novo ACTB c.547C>T (p.Arg183Trp) variant in 39-years-old Czech male case with complex dystonia (age of onset at 24 years) who had additional clinical features (but with normal brain MRI). The variant absence in parents has been confirmed through Sanger sequencing.

Eggink, et al. (2017, PMID 27862284) presented a family with dystonia. Whole-exome-sequencing revealed ACTB c.547C>T (p.Arg183Trp) variant in 2 family members: 22 years old female with dystonia (age of onset at 19 years) who in addition to other clinical features showed high-arched eyebrows (but with normal brain MRI results); her 49 years old mother with dystonia (who at age 16 experienced hands trembling, at age 21 she had writer’s cramp diagnosed) and additional clinical features.

Cuvertino, et al. (2017, PMID 29220674) analyzed data of more than 15,000 suspected genetic development disorder individuals, 26 cases with 7p22.1 deletions and 4,293 trios from the Deciphering Developmental Disorders study. The ACTB c.1097dupG (p.Ser368Leufs*13) variant has been found de novo in 12 years old heterozygous male case (of United Kingdom origin; Table S1) who had dystonia (as well as additional clinical features; Table 1). This variant was absent from gnomAD v2.1.1 as of December 2021.
(Please note that ACTB c.1097dupG (p.Ser368Leufs*13) results in extension of protein)

Hundt, et al. (2014, PMID 25255767) presented in vitro functional study on Sf9 cells. The results showed that ACTB c.547C>T (p.Arg183Trp) variant resulted in 3 times higher inhibition of DNase I-mediated nucleic acid cleavage (p < 0.0001; Fig.2A), unchanged thermal stability (Fig. 2B), nucleotide exchange from actin monomer was 2.4 times slower (p = 0.0113; Fig.3), 1.9 times faster half-time polymerization (p = 0.0006; Fig. 4A), 1.7 times higher ATP turnover (Fig. 4B), significantly reduced half-time of the depolymerization (Fig. 4C), close to normal binding to the profilin II (Fig. 5A), 4 times lower ability to activate ATPase of nonmuscle myosin-2A isoform (Fig. 6), in comparison to the wild-type. The authors also carried out the computational analysis and showed that this variant impaired the opening of the nucleotide cleft (Fig. 7C, Fig. 8B).; to: Freitas, et al. (2020, PMID: 31970217) presented 52 years of age Brazilian female case with dystonia (onset at age of 25 years) who had additional clinical features (but without facial dysmorphism and brain abnormalities). Whole-exome-sequencing showed the presence of ACTB c.547C>T (p.Arg183Trp) variant. This variant was absent from gnomAD v2.1.1 as of December 2021.

Skogseid, et al. (2018, PMID: 29788902) presented 23 years old female case with dystonia (age at onset 13 years), mild dysmorphic facial traits and additional clinical features (but with grossly maintained brain structure). Whole-exome-sequencing revealed heterozygous ACTB c.547C>T (p.Arg183Trp) variant. The case was negative for the aCGH analysis.

Zech, et al. (2017, PMID: 28849312) presented 9 unrelated cases with combined and/or complex dystonia (8 of European and 1 of Asian origin). Whole-exome-sequencing revealed de novo ACTB c.547C>T (p.Arg183Trp) variant in 39-years-old Czech male case with complex dystonia (age of onset at 24 years) who had additional clinical features (but with normal brain MRI). The variant absence in parents has been confirmed through Sanger sequencing.

Eggink, et al. (2017, PMID: 27862284) presented a family with dystonia. Whole-exome-sequencing revealed ACTB c.547C>T (p.Arg183Trp) variant in 2 family members: 22 years old female with dystonia (age of onset at 19 years) who in addition to other clinical features showed high-arched eyebrows (but with normal brain MRI results); her 49 years old mother with dystonia (who at age 16 experienced hands trembling, at age 21 she had writer’s cramp diagnosed) and additional clinical features.

Cuvertino, et al. (2017, PMID: 29220674) analyzed data of more than 15,000 suspected genetic development disorder individuals, 26 cases with 7p22.1 deletions and 4,293 trios from the Deciphering Developmental Disorders study. The ACTB c.1097dupG (p.Ser368Leufs*13) variant has been found de novo in 12 years old heterozygous male case (of United Kingdom origin; Table S1) who had dystonia (as well as additional clinical features; Table 1). This variant was absent from gnomAD v2.1.1 as of December 2021.
(Please note that ACTB c.1097dupG (p.Ser368Leufs*13) results in extension of protein)

Hundt, et al. (2014, PMID: 25255767) presented in vitro functional study on Sf9 cells. The results showed that ACTB c.547C>T (p.Arg183Trp) variant resulted in 3 times higher inhibition of DNase I-mediated nucleic acid cleavage (p < 0.0001; Fig.2A), unchanged thermal stability (Fig. 2B), nucleotide exchange from actin monomer was 2.4 times slower (p = 0.0113; Fig.3), 1.9 times faster half-time polymerization (p = 0.0006; Fig. 4A), 1.7 times higher ATP turnover (Fig. 4B), significantly reduced half-time of the depolymerization (Fig. 4C), close to normal binding to the profilin II (Fig. 5A), 4 times lower ability to activate ATPase of nonmuscle myosin-2A isoform (Fig. 6), in comparison to the wild-type. The authors also carried out the computational analysis and showed that this variant impaired the opening of the nucleotide cleft (Fig. 7C, Fig. 8B).
Early onset dystonia v1.99 ACTB Eldar Dedic reviewed gene: ACTB: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31970217, 29788902, 28849312, 27862284, 29220674, 25255767; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset dystonia v1.99 ACTB Eldar Dedic Deleted their review
Early onset dystonia v1.99 ACTB Eldar Dedic reviewed gene: ACTB: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: 31970217, 29788902, 28849312, 27862284, 29220674, 25255767; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia with onset in adulthood v2.133 RFC1 Dmitrijs Rots changed review comment from: Only STR in this gene is associated with CANVAS / ataxia. Addition of this gene to the panel will result only in unnecessary load of RFC1 SNV/indel/CNV analysis, which are not related to human disorder.; to: Only STR in this gene is associated with CANVAS / ataxia. Addition of this gene to the panel will result only in unnecessary load of RFC1 SNV/indel/CNV analysis, which are not related to human disorder.
Additionallly, RFC1 repeat expansion, is commonly associated with sensory neuropathy (at the moment of presentation usually without clinically prominent ataxia) ,so the STR should be added to the neuropathy panel as well, not just ataxia (PMID: 33969391).
Hereditary ataxia with onset in adulthood v2.133 RFC1 Dmitrijs Rots reviewed gene: RFC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1475 ANK3 Dmitrijs Rots reviewed gene: ANK3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34218362; Phenotypes: Intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.133 RFC1 Eleanor Williams Classified gene: RFC1 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v2.133 RFC1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but noting that it is repeat expansions within an intron that is associated with the CANVAS phenotype, not SNVs within the protein coding region. Added to the list of STRs to be added.
Hereditary ataxia with onset in adulthood v2.133 RFC1 Eleanor Williams Gene: rfc1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v2.132 RFC1 Eleanor Williams Phenotypes for gene: RFC1 were changed from Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome OMIM 614575 to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM:614575; cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, MONDO:0013809; chronic idiopathic axonal polyneuropathy; chronic polyneuropathy, MONDO:0003335
Hereditary ataxia with onset in adulthood v2.131 RFC1 Eleanor Williams Publications for gene: RFC1 were set to 30926972
Hereditary ataxia with onset in adulthood v2.130 RFC1 Eleanor Williams Tag STR tag was added to gene: RFC1.
Hereditary ataxia with onset in adulthood v2.130 RFC1 Eleanor Williams changed review comment from: The gene is associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) #614575 (AR) with two repeat expansions cited as the allelic variants.

PMID: 30926972 - Cortese et al 2019 - found a recessive intronic AAGGG repeat expansion in the RFC1 gene as a cause of familial CANVAS in 11 families. 4 SNPs around RFC1 were shared by all individuals except in family 5, suggesting a founder haplotype. They found an additional 33 sporadic cases carrying the recessive AAGGG repeat expansion in a cohort of 150 patients diagnosed with sporadic late-onset ataxia (22%). They also note that all sporadic cases with the repeat expansion, except for one individual, shared the same haplotype as familial CANVAS cases. Although the expansion size varied across different families, ranging from around 400 to 2000 repeats, in the majority of cases approximately 1000 repeats were observed. In 304 healthy controls, 4/608 chromosomes (0.7%) chromosomes carried an AAGGG expansion in the heterozygous state. 3 other conformations were observed: (AAAAG)11 (75.5%); (AAAAG)exp(13.0%); and (AAAGG)exp (7.9%). They did not observe a reduced level of RFC1 expression at either the transcript or the protein level in CANVAS patients.

PMID: 31824583 - Akçimen et al 2019 - looked at RFC1 repeat expansions in cohort of Brazilian cases and two cohorts of Canadian cases. 1 Brazilian and 1 Canadian case were found to carry the causative biallelic AAGGG repeat expansion. Two novel repeat sequences were found in the heterozygous state; AAGAG and AGAGG.

PMID: 32851396 - Beecroft et al 2020 - describe a (AAAGG)10-25(AAGGG)exp found in New Zealand Māori and Cook Island Māori individuals which was the cause of CANVAS in all patients. Patients in 2 families also had small number of repeats of the benign variant allele (AAAGG)4-6 at the distal end of the RFC1 pathogenic expansion. The 4 patients with WGS data were found to share the same core haplotype as described in European populations in Cortese et al 2019, plus an additional region.

PMID: 32582864 - Syriani et al 2020 - 29 patients from North America were identified with biallelic repeat expansions in RFC1 (AAGGG) (3.2% of total). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%).

PMID: 33969391 - Curro et al 2021 - retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy). Patients previously diagnosed with CANVAS or with a family history of CANVAS were not included. 43 patients (34%) with sensory neuropathy had biallelic AAGGG repeat expansions in RFC1and in none with sensory-motor neuropathy.; to: The gene is associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) #614575 (AR) with two repeat expansions cited as the allelic variants.

There is data to suggest a common haplotype between most cases but this appears to be quite ancient (25000 yo) and so the cases from individuals from different countries can probably be counted as being unrelated. The mechanism of action of this intronic repeat expansion is not yet known.

= AAGGG repeat expansion =

PMID: 30926972 - Cortese et al 2019 - found a recessive intronic AAGGG repeat expansion in the RFC1 gene as a cause of familial CANVAS in 11 families. 4 SNPs around RFC1 were shared by all individuals except in family 5, suggesting a founder haplotype. They found an additional 33 sporadic cases carrying the recessive AAGGG repeat expansion in a cohort of 150 patients diagnosed with sporadic late-onset ataxia (22%). They also note that all sporadic cases with the repeat expansion, except for one individual, shared the same haplotype as familial CANVAS cases. Although the expansion size varied across different families, ranging from around 400 to 2000 repeats, in the majority of cases approximately 1000 repeats were observed. In 304 healthy controls, 4/608 chromosomes (0.7%) chromosomes carried an AAGGG expansion in the heterozygous state. 3 other conformations were observed: (AAAAG)11 (75.5%); (AAAAG)exp(13.0%); and (AAAGG)exp (7.9%). They did not observe a reduced level of RFC1 expression at either the transcript or the protein level in CANVAS patients.

PMID: 31824583 - Akçimen et al 2019 - looked at RFC1 repeat expansions in cohort of Brazilian cases and two cohorts of Canadian cases. 1 Brazilian and 1 Canadian case were found to carry the causative biallelic AAGGG repeat expansion. Two novel repeat sequences were found in the heterozygous state; AAGAG and AGAGG.

PMID: 31230722 - Rafehi et al 2019 - bioinformatics paper looking at using Expansion Hunter de novo on WGS data but also reports RFC1 (AAGGG)exp in 18/22 CANVAS families. Also states that the core ancestral haplotype is estimated to have arisen in Europe more than twenty-five thousand years ago.

PMID: 32851396 - Beecroft et al 2020 - describe a (AAAGG)10-25(AAGGG)exp found in New Zealand Māori and Cook Island Māori individuals which was the cause of CANVAS in all patients. Patients in 2 families also had small number of repeats of the benign variant allele (AAAGG)4-6 at the distal end of the RFC1 pathogenic expansion. The 4 patients with WGS data were found to share the same core haplotype as described in European populations in Cortese et al 2019, plus an additional region.

PMID: 32582864 - Syriani et al 2020 - 29 patients from North America were identified with biallelic repeat expansions in RFC1 (AAGGG) (3.2% of total). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%).

PMID: 32694621 - Tsuchiya et al 2020 - found intronic (AAGGG) repeat expansions in RFC1 in 3 (12%) of the familial Japanese patients with CANVAS and 1 (8.5%) of the sporadic ones.

PMID: 33969391 - Curro et al 2021 - retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy). Patients previously diagnosed with CANVAS or with a family history of CANVAS were not included. 43 patients (34%) with sensory neuropathy had biallelic AAGGG repeat expansions in RFC1and in none with sensory-motor neuropathy.

= ACAGG repeat expansion =

PMID: 33103729 - Scriba et al 2020 - report 3 patients with CANVAS from 2 families (2 brothers who reside in Indonesia, but are of Chinese descent, and a isolated female proband from the island nation of Niue) , with a novel, likely pathogenic RFC1 repeat motif (ACAGG)exp. These patients show additional clinical features including fasciculations and elevated creatine kinase levels. They share the core haplotype described in Cortese et al 2019 and Beecroft et al 2020. The RFC1 (ACAGG) motif was found in 7 individuals from 26 745 samples from gnomAD v3; 2 African, 4 South Asian, 1 East Asian.

PMID: 32694621 - Tsuchiya et al 2020 - reports a RFC1 (ACAGG) exp in 1 Japanese individual with sporadic CANVAS.
DDG2P v2.53 FGF5 Anna de Burca gene: FGF5 was added
gene: FGF5 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: FGF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGF5 were set to PMID: 24989505
Phenotypes for gene: FGF5 were set to Hypertrichosis; long eyelashes
Penetrance for gene: FGF5 were set to Complete
Review for gene: FGF5 was set to GREEN
Added comment: Segregates with phenotype in two consanguineous families in publication attached. Additional unpublished case with same phenotype.
Sources: Literature
Hereditary ataxia with onset in adulthood v2.130 RFC1 Eleanor Williams reviewed gene: RFC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30926972, 31824583, 32851396, 32582864, 33969391; Phenotypes: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM:614575, cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, MONDO:0013809, chronic idiopathic axonal polyneuropathy, chronic polyneuropathy, MONDO:0003335; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.53 CNKSR2 Dmitrijs Rots reviewed gene: CNKSR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34266427; Phenotypes: Developmental delay, intellectual disability, seizures; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Ataxia and cerebellar anomalies - narrow panel v2.278 COQ4 Dmitrijs Rots gene: COQ4 was added
gene: COQ4 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: COQ4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ4 were set to PMID: 30225196; 33704555; 30847826
Phenotypes for gene: COQ4 were set to Childhood onset ataxia
Penetrance for gene: COQ4 were set to Complete
Review for gene: COQ4 was set to GREEN
Added comment: The phenotype of COQ4 deficiency is very broad. In the three publications, at 6 individuals from 4 families are reported as having childhood onset ataxia.
Sources: Literature
Hereditary Erythrocytosis v1.35 SH2B3 Dmitrijs Rots reviewed gene: SH2B3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 34440325, 34021251; Phenotypes: Myeloproliferative neoplasm; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary Erythrocytosis v1.35 SLC30A10 Dmitrijs Rots gene: SLC30A10 was added
gene: SLC30A10 was added to Hereditary Erythrocytosis. Sources: Literature
Mode of inheritance for gene: SLC30A10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A10 were set to PMID: 22341971; 22341972
Phenotypes for gene: SLC30A10 were set to Erythrocytosis; Polycytemia; Hypermanganesemia; Parkinsonism; Dystonia; Liver disease
Review for gene: SLC30A10 was set to GREEN
Added comment: In 6 individuals from two families and 14 individuals from 8 families reported in in 22341971 and 22341972, respectively - all have erythrocytosis/polycytemia.
Sources: Literature
Hereditary Erythrocytosis v1.35 PIEZO1 Dmitrijs Rots gene: PIEZO1 was added
gene: PIEZO1 was added to Hereditary Erythrocytosis. Sources: Literature
Mode of inheritance for gene: PIEZO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIEZO1 were set to PMID: 33181827
Phenotypes for gene: PIEZO1 were set to Erythrocytosis
Penetrance for gene: PIEZO1 were set to unknown
Mode of pathogenicity for gene: PIEZO1 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: PIEZO1 was set to GREEN
Added comment: Pathogenic variants (gain-of-function missense) in the PIEZO1 has been previously identified as a cause of hereditary xerocytosis. Recently, it has been Identified that similar (likely) pathogenic GoF missense variants likely causes erythrocytosis in 5 individuals. Functional analysis confirms pathogenicity of the variants. Patients also displayed features of hereditary xerocytosis.
Sources: Literature
Hereditary Erythrocytosis v1.35 BPGM Dmitrijs Rots reviewed gene: BPGM: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29790589; Phenotypes: Erythrocytosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.67 HEXB Dmitrijs Rots reviewed gene: HEXB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20472204; Phenotypes: Sandhoff disease, neuropathy, ataxia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Corneal dystrophy v1.7 TCF4 Dmitrijs Rots reviewed gene: TCF4: Rating: RED; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: None
Corneal dystrophy v1.7 TCF4 Sarah Leigh Added comment: Comment on publications: Also https://doi.org/10.3390/genes12121918 (no PMID available 30th Dec 2021).
Corneal dystrophy v1.7 TCF4 Sarah Leigh Publications for gene: TCF4 were set to 29526280; 26401622
Malformations of cortical development v2.100 ENO1 Ivone Leong Classified gene: ENO1 as Red List (low evidence)
Malformations of cortical development v2.100 ENO1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Malformations of cortical development v2.100 ENO1 Ivone Leong Gene: eno1 has been classified as Red List (Low Evidence).
Malformations of cortical development v2.99 ENO1 Ivone Leong Phenotypes for gene: ENO1 were changed from Polymicrogyria to Polymicrogyria, MONDO:0000087
Hereditary neuropathy or pain disorder v1.67 HEXB Evan Reid edited their review of gene: HEXB: Changed rating: GREEN
Hereditary neuropathy or pain disorder v1.67 HEXA Evan Reid gene: HEXA was added
gene: HEXA was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: HEXA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEXA were set to PMID: 28739864; 18642377
Penetrance for gene: HEXA were set to Complete
Review for gene: HEXA was set to GREEN
Added comment: Both HEXA and HEXB autosomal recessive mutations can be associated with a late onset motor neuropathy, sometimes quite mild and sometimes resembling ALS. We missed diagnosis of a patient with a late onset motor neuropathy as HEXB is not on the neuropathy panel. I would suggest that HEXA and HEXB should both be included on this panel.
Sources: Literature
Hereditary neuropathy or pain disorder v1.67 HEXB Evan Reid reviewed gene: HEXB: Rating: ; Mode of pathogenicity: None; Publications: PMID: 31512525, 20798201, 2795083; Phenotypes: ALS, motor neuronopathy; Mode of inheritance: None
Hereditary neuropathy or pain disorder v1.67 HEXB Evan Reid gene: HEXB was added
gene: HEXB was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: HEXB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEXB were set to PMID: 31512525
Penetrance for gene: HEXB were set to Complete
Pigmentary skin disorders v1.37 SMARCAL1 Ivone Leong Tag Q4_21_NHS_review tag was added to gene: SMARCAL1.
Pigmentary skin disorders v1.37 TFE3 Ivone Leong Tag Q4_21_NHS_review tag was added to gene: TFE3.
Pigmentary skin disorders v1.37 USP9X Ivone Leong Tag Q4_21_rating tag was added to gene: USP9X.
Tag Q4_21_NHS_review tag was added to gene: USP9X.
Pigmentary skin disorders v1.37 USP9X Ivone Leong Classified gene: USP9X as Amber List (moderate evidence)
Pigmentary skin disorders v1.37 USP9X Ivone Leong Added comment: Comment on list classification: New gene added by Tom Cullup (Great Ormond Street Hospital). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). There is enough evidence to support a gene-disease association, this gene should be rated Green at the next review.
Pigmentary skin disorders v1.37 USP9X Ivone Leong Gene: usp9x has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v1.36 USP9X Ivone Leong Phenotypes for gene: USP9X were changed from Intellectual developmental disorder, X-linked 99, syndromic, female-restricted, OMIM:300968; Intellectual developmental disorder, X-linked 99, OMIM:300072 to Intellectual developmental disorder, X-linked 99, syndromic, female-restricted, OMIM:300968
Pigmentary skin disorders v1.35 USP9X Ivone Leong Phenotypes for gene: USP9X were changed from INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 99, SYNDROMIC, FEMALE-RESTRICTED to Intellectual developmental disorder, X-linked 99, syndromic, female-restricted, OMIM:300968; Intellectual developmental disorder, X-linked 99, OMIM:300072
Pigmentary skin disorders v1.34 TFE3 Ivone Leong Tag Q4_21_rating tag was added to gene: TFE3.
Pigmentary skin disorders v1.34 TFE3 Ivone Leong Classified gene: TFE3 as Amber List (moderate evidence)
Pigmentary skin disorders v1.34 TFE3 Ivone Leong Added comment: Comment on list classification: New gene added by Tom Cullup (Great Ormond Street Hospital). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (confirmed). There is enough evidence to support a gene-disease association (12/17 patients have skin pigmentation abnormalities), this gene should be Green at the next review.
Pigmentary skin disorders v1.34 TFE3 Ivone Leong Gene: tfe3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1475 HMGB1 Dmitrijs Rots reviewed gene: HMGB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v2.53 PBX1 Dmitrijs Rots gene: PBX1 was added
gene: PBX1 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: PBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PBX1 were set to Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay
Review for gene: PBX1 was set to GREEN
Added comment: Syndromic gene. Most of the individuals present with developmental delay, according to OMIM.
Sources: Literature
Monogenic hearing loss v2.209 PBX1 Dmitrijs Rots gene: PBX1 was added
gene: PBX1 was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: PBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PBX1 were set to Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay
Review for gene: PBX1 was set to GREEN
Added comment: Well known disease gene. As OMIM disease name suggests, hearing loss with ear abnormalities is common (reported in at least 5 cases).
Sources: Literature
Pigmentary skin disorders v1.33 TFE3 Ivone Leong Phenotypes for gene: TFE3 were changed from Intellectual disability with pigmentary mosaicism and storage disorder-like features to Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, OMIM:301066
Pigmentary skin disorders v1.32 SMARCAL1 Ivone Leong Tag Q4_21_rating tag was added to gene: SMARCAL1.
Pigmentary skin disorders v1.32 SMARCAL1 Ivone Leong Classified gene: SMARCAL1 as Amber List (moderate evidence)
Pigmentary skin disorders v1.32 SMARCAL1 Ivone Leong Added comment: Comment on list classification: New gene added by Tom Cullup (Great Ormond Street Hospital). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (confirmed). There are >3 unrelated cases and PMID:20301550 reports that ~70% of patients have hyperpigmented macules. Therefore, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Pigmentary skin disorders v1.32 SMARCAL1 Ivone Leong Gene: smarcal1 has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v1.31 SMARCAL1 Ivone Leong Publications for gene: SMARCAL1 were set to 11799392
Pigmentary skin disorders v1.30 SMARCAL1 Ivone Leong Phenotypes for gene: SMARCAL1 were changed from SCHIMKE IMMUNOOSSEOUS DYSPLASIA to Schimke immunoosseous dysplasia, OMIM:242900
IUGR and IGF abnormalities v1.46 PAPPA2 Ivone Leong Added comment: Comment on publications: Added new publication PMID:33875846
IUGR and IGF abnormalities v1.46 PAPPA2 Ivone Leong Publications for gene: PAPPA2 were set to 26902202
IUGR and IGF abnormalities v1.45 KANSL1 Ivone Leong Classified gene: KANSL1 as Green List (high evidence)
IUGR and IGF abnormalities v1.45 KANSL1 Ivone Leong Added comment: Comment on list classification: New gene added by Andžela Lazdāne (Children's Clinical University Hospital of Latvia). This gene is assiociated with a relevant phenotype in OMIM and Gene2Phenotype (confirmed). There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
IUGR and IGF abnormalities v1.45 KANSL1 Ivone Leong Gene: kansl1 has been classified as Green List (High Evidence).
IUGR and IGF abnormalities v1.44 KANSL1 Ivone Leong Added comment: Comment on publications: PMID: 26306646. Additional 12 cases with de novo variants in KANSL1 causing disease, which further indicates that haploinsufficiency for KANSL1 is sufficient to cause the core phenotype.
IUGR and IGF abnormalities v1.44 KANSL1 Ivone Leong Publications for gene: KANSL1 were set to 22544363
IUGR and IGF abnormalities v1.43 KANSL1 Ivone Leong Publications for gene: KANSL1 were set to PMID: 22544363
IUGR and IGF abnormalities v1.42 KANSL1 Ivone Leong Phenotypes for gene: KANSL1 were changed from Koolen-De Vries syndrome; Facial features; Delayed psychomotor development; Intellectual disability to Koolen-De Vries syndrome, OMIM:610443; Facial features; Delayed psychomotor development; Intellectual disability
Primary ovarian insufficiency v1.60 SYCE1 Ivone Leong Classified gene: SYCE1 as Green List (high evidence)
Primary ovarian insufficiency v1.60 SYCE1 Ivone Leong Added comment: Comment on list classification: This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association (2 cases + 1 animal model). Therefore, this gene has been promoted from Amber to Green.
Primary ovarian insufficiency v1.60 SYCE1 Ivone Leong Gene: syce1 has been classified as Green List (High Evidence).
Primary ovarian insufficiency v1.59 SYCE1 Ivone Leong Added comment: Comment on publications: PMID: 32917591. Authors made knockin mice with the mouse equivalent variant as Q241X seen in PMID:25062452. Both male and female homozygous mutant mice were infertile and replicated the human phenotype.

PMID:34718620. An additional case. Patient is compound heterozygous for variants in SYCE1.
Primary ovarian insufficiency v1.59 SYCE1 Ivone Leong Publications for gene: SYCE1 were set to 25062452
Primary ovarian insufficiency v1.58 SYCE1 Ivone Leong Phenotypes for gene: SYCE1 were changed from Premature ovarian failure 12616947 to ?Premature ovarian failure 12, OMIM:616947
Primary ovarian insufficiency v1.57 C14orf39 Ivone Leong Classified gene: C14orf39 as Green List (high evidence)
Primary ovarian insufficiency v1.57 C14orf39 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. There is now enough evidence to support a gene-disease association (2 cases + 1 animal model). This gene has been promoted to Green.
Primary ovarian insufficiency v1.57 C14orf39 Ivone Leong Gene: c14orf39 has been classified as Green List (High Evidence).
Primary ovarian insufficiency v1.56 C14orf39 Ivone Leong Publications for gene: C14orf39 were set to 33508233; 27796301
Intellectual disability v3.1475 PHF6 Ivone Leong reviewed gene: PHF6: Rating: ; Mode of pathogenicity: None; Publications: 24092917, 25099957; 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)
Intellectual disability v3.1475 PHF6 Ivone Leong Phenotypes for gene: PHF6 were changed from Borjeson-Forssman-Lehmann syndrome, 301900; BOERJESON-FORSSMAN-LEHMANN SYNDROME (BFLS) to Borjeson-Forssman-Lehmann syndrome, OMIM:301900
Intellectual disability v3.1474 PHF6 Ivone Leong Publications for gene: PHF6 were set to
Intellectual disability v3.1473 PHF6 Ivone Leong Tag Q4_21_MOI tag was added to gene: PHF6.
DDG2P v2.53 PHF6 Ivone Leong reviewed gene: PHF6: Rating: ; Mode of pathogenicity: None; Publications: 24092917, 25099957; 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)
Fetal anomalies v1.819 PHF6 Ivone Leong Tag Q4_21_MOI tag was added to gene: PHF6.
Fetal anomalies v1.819 PHF6 Ivone Leong reviewed gene: PHF6: Rating: ; Mode of pathogenicity: None; Publications: 24092917, 25099957; 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)
Fetal anomalies v1.819 PHF6 Ivone Leong Publications for gene: PHF6 were set to
Fetal anomalies v1.818 PHF6 Ivone Leong Phenotypes for gene: PHF6 were changed from BOERJESON-FORSSMAN-LEHMANN SYNDROME to Borjeson-Forssman-Lehmann syndrome, OMIM:301900
Severe early-onset obesity v2.46 PHF6 Ivone Leong Tag Q4_21_MOI tag was added to gene: PHF6.
Severe early-onset obesity v2.46 PHF6 Ivone Leong reviewed gene: PHF6: Rating: ; Mode of pathogenicity: None; Publications: 24092917, 25099957; 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)
Severe early-onset obesity v2.46 PHF6 Ivone Leong Publications for gene: PHF6 were set to
Pigmentary skin disorders v1.29 PHF6 Ivone Leong Publications for gene: PHF6 were set to 24092917
Pigmentary skin disorders v1.28 PHF6 Ivone Leong Tag Q4_21_rating tag was added to gene: PHF6.
Tag Q4_21_NHS_review tag was added to gene: PHF6.
Pigmentary skin disorders v1.28 PHF6 Ivone Leong Classified gene: PHF6 as Amber List (moderate evidence)
Pigmentary skin disorders v1.28 PHF6 Ivone Leong Added comment: Comment on list classification: New gene added by Tom Cullup (Great Ormond Street Hospital). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (confirmed). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Pigmentary skin disorders v1.28 PHF6 Ivone Leong Gene: phf6 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.121 RNASEH2B Arina Puzriakova Publications for gene: RNASEH2B were set to 30223285; 25243380; 29691679; 28762473
Childhood onset hereditary spastic paraplegia v2.120 RNASEH2B Arina Puzriakova Classified gene: RNASEH2B as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.120 RNASEH2B Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence of childhood-onset spasticity associated with variants in this gene. Upgraded from Red to Amber but should be promoted to Green at the next GMS panel update.
Childhood onset hereditary spastic paraplegia v2.120 RNASEH2B Arina Puzriakova Gene: rnaseh2b has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.119 RNASEH2B Arina Puzriakova Tag Q4_21_rating tag was added to gene: RNASEH2B.
Pigmentary skin disorders v1.27 PHF6 Ivone Leong Phenotypes for gene: PHF6 were changed from BORJESON-FORSSMAN-LEHMANN SYNDROME; Fine and whorled Blaschko-linear hypo or hyperpigmentation to Borjeson-Forssman-Lehmann syndrome, OMIM:301900; Fine and whorled Blaschko-linear hypo or hyperpigmentation
Childhood onset hereditary spastic paraplegia v2.119 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2, 610181; spastic paraparesis to Aicardi-Goutieres syndrome 2, OMIM:61018
Pigmentary skin disorders v1.26 NDUFB11 Ivone Leong Tag Q4_21_expert_review tag was added to gene: NDUFB11.
Tag Q4_21_NHS_review tag was added to gene: NDUFB11.
Pigmentary skin disorders v1.26 NDUFB11 Ivone Leong Classified gene: NDUFB11 as Amber List (moderate evidence)
Pigmentary skin disorders v1.26 NDUFB11 Ivone Leong Added comment: Comment on list classification: New gene added by Tom Cullup (Great Ormond Street Hospital). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). There is currently only 2 published cases of patients with Linear skin defects with multiple congenital anomalies 3. This gene is also associated with Histiocytoid cardiomyopathy and Lactic acidosis and sideroblastic anemia and patients with these diseases do not have signs of skin defects. Therefore, there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Pigmentary skin disorders v1.26 NDUFB11 Ivone Leong Gene: ndufb11 has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v1.25 NDUFB11 Ivone Leong Phenotypes for gene: NDUFB11 were changed from Linear Skin Defects with Multiple Congenital Anomalies to Linear skin defects with multiple congenital anomalies 3, OMIM:300952
Early onset dystonia v1.99 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Dystonia to Aicardi-Goutieres syndrome 2, OMIM:61018
White matter disorders and cerebral calcification - narrow panel v1.220 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres Syndrome; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Aicardi-Goutieres syndrome 2 to Aicardi-Goutieres syndrome 2, OMIM:610181
Adult onset leukodystrophy v1.36 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2, 610181 to Aicardi-Goutieres syndrome 2, OMIM:610181
Primary immunodeficiency or monogenic inflammatory bowel disease v2.498 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2 610181; Type 1 interferonopathies; Classical AGS, SP; Autoinflammatory Disorders to Aicardi-Goutieres syndrome 2, OMIM:610181
Intracerebral calcification disorders v1.34 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2; Aicardi-Goutieres Syndrome to Aicardi-Goutieres syndrome 2, OMIM:610181
Inherited white matter disorders v1.150 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres Syndrome; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Aicardi-Goutieres syndrome 2 to Aicardi-Goutieres syndrome 2, OMIM:610181
Hereditary spastic paraplegia v1.276 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2, 610181; spastic paraparesis to Aicardi-Goutieres syndrome 2, OMIM:610181
Likely inborn error of metabolism v2.203 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Intellectual disability; (Disorders of nucleotide metabolism, Aicardi-Gouti res Syndrome) AGS2; Intracerebral calcification disorders; Inherited white matter disorders to Aicardi-Goutieres syndrome 2, OMIM:610181
Adult onset neurodegenerative disorder v2.257 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Dystonia to Aicardi-Goutieres syndrome 2, OMIM:610181; Dystonia (onset in infancy)
Undiagnosed metabolic disorders v1.501 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from (Disorders of nucleotide metabolism, Aicardi-Gouti res Syndrome) AGS2; Inherited white matter disorders; Intellectual disability; Intracerebral calcification disorders to Aicardi-Goutieres syndrome 2, OMIM:610181
Intellectual disability v3.1473 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2, 610181; AICARDI-GOUTIERES SYNDROME 2 to Aicardi-Goutieres syndrome 2, OMIM:610181
Fetal anomalies v1.817 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from AICARDI-GOUTIERES SYNDROME 2 to Aicardi-Goutieres syndrome 2, OMIM:610181
Early onset or syndromic epilepsy v2.477 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2, 610181 to Aicardi-Goutieres syndrome 2, OMIM:610181
Adult onset dystonia, chorea or related movement disorder v1.161 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2, 610181; Dystonia to Aicardi-Goutieres syndrome 2, OMIM:610181; Dystonia (onset in infancy)
Adult onset dystonia, chorea or related movement disorder v1.160 RNASEH2B Arina Puzriakova Mode of inheritance for gene: RNASEH2B was changed from to BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.204 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2, 610181 to Aicardi-Goutieres syndrome 2, OMIM:610181
Childhood onset hereditary spastic paraplegia v2.118 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from spastic paraplegia to Martsolf syndrome 1, OMIM:212720
Hereditary spastic paraplegia v1.275 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from spastic paraplegia; Warburg micro syndrome 2, 614225 to Martsolf syndrome 1, OMIM:212720; Warburg micro syndrome 2, OMIM:614225
Adult onset hereditary spastic paraplegia v1.88 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from spastic paraplegia; Warburg micro syndrome 2, 614225 to Warburg micro syndrome 2, OMIM:614225
Early onset or syndromic epilepsy v2.476 RAB3GAP2 Arina Puzriakova Mode of inheritance for gene: RAB3GAP2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.475 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from to Martsolf syndrome 1, OMIM:212720; Warburg micro syndrome 2, OMIM:614225
Malformations of cortical development v2.98 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from Warburg micro syndrome 2, MIM# 614225 to Warburg micro syndrome 2, OMIM:614225
Adult onset neurodegenerative disorder v2.256 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from spastic paraplegia to Martsolf syndrome 1, OMIM:212720
Skeletal dysplasia v2.159 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from Martsolf syndrome to Martsolf syndrome 1, OMIM:212720
Skeletal dysplasia v2.158 RAB3GAP2 Arina Puzriakova Mode of inheritance for gene: RAB3GAP2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Dilated Cardiomyopathy and conduction defects v1.75 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from 212720; 614225 to Martsolf syndrome 1, OMIM:212720; Warburg micro syndrome 2, OMIM:614225
Corneal abnormalities v1.10 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from Martsolf syndrome 212720; Warburg micro syndrome 2 614225 to Martsolf syndrome 1, OMIM:212720; Warburg micro syndrome 2, OMIM:614225
Structural eye disease v1.94 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from Martsolf syndrome, 212720; Warburg micro syndrome 2, 614225; Martsolf syndrome, 212720Warburg micro syndrome 2, 614225; Warburg Micro Syndrome to Martsolf syndrome 1, OMIM:212720; Warburg micro syndrome 2, OMIM:614225
Anophthalmia or microphthalmia v1.43 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from Warburg Micro Syndrome; Martsolf syndrome, 212720Warburg micro syndrome 2, 614225 to Martsolf syndrome 1, OMIM:212720; Warburg micro syndrome 2, OMIM:614225
Intellectual disability v3.1472 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from Martsolf syndrome, 212720Warburg micro syndrome 2, 614225; MARTSOLF SYNDROME (MARTS) to Martsolf syndrome 1, OMIM:212720; Warburg micro syndrome 2, OMIM:614225
Bilateral congenital or childhood onset cataracts v2.90 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from Martsolf syndrome; Warburg micro syndrome 2; Warburg Micro syndrome-2 to Martsolf syndrome 1, OMIM:212720; Warburg micro syndrome 2, OMIM:614225
Ataxia and cerebellar anomalies - narrow panel v2.278 MAPK8IP3 Arina Puzriakova Classified gene: MAPK8IP3 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.278 MAPK8IP3 Arina Puzriakova Added comment: Comment on list classification: 18 individuals from 17 families reported with de novo variants in this gene (PMIDs: 30612693; 30945334) of which 3 subjects displayed cerebellar atrophy on brain MRI and 2 had ataxia. Onset in childhood. Overall there is sufficient evidence to promote this gene to Green at the next GMS panel update.
Ataxia and cerebellar anomalies - narrow panel v2.278 MAPK8IP3 Arina Puzriakova Gene: mapk8ip3 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v2.130 MAPK8IP3 Arina Puzriakova Classified gene: MAPK8IP3 as Green List (high evidence)
Hereditary ataxia with onset in adulthood v2.130 MAPK8IP3 Arina Puzriakova Added comment: Comment on list classification: 18 individuals from 17 families reported with de novo variants in this gene (PMIDs: 30612693; 30945334) of which 3 subjects displayed cerebellar atrophy on brain MRI and 2 had ataxia. However, this is a childhood onset condition and literature search did not reveal any evidence of adult onset ataxia associated with this gene. Therefore, MAPK8IP3 should be downgraded from Green here and added to the childhood cerebellar anomalies panel.
Hereditary ataxia with onset in adulthood v2.130 MAPK8IP3 Arina Puzriakova Gene: mapk8ip3 has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.277 MAPK8IP3 Arina Puzriakova Entity copied from Hereditary ataxia - adult onset v2.129
Ataxia and cerebellar anomalies - narrow panel v2.277 MAPK8IP3 Arina Puzriakova gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Wessex and West Midlands GLH,Expert Review Green,NHS GMS
Q4_21_rating tags were added to gene: MAPK8IP3.
Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK8IP3 were set to 30612693; 30945334
Phenotypes for gene: MAPK8IP3 were set to Neurodevelopmental disorder with or without variable brain abnormalities, OMIM:618443
Hereditary ataxia with onset in adulthood v2.129 MAPK8IP3 Arina Puzriakova Publications for gene: MAPK8IP3 were updated from to 30612693; 30945334
Tag Q4_21_rating tag was added to MAPK8IP3.
Childhood onset hereditary spastic paraplegia v2.117 MAPK8IP3 Arina Puzriakova Phenotypes for gene: MAPK8IP3 were changed from Neurodevelopmental disorder with or without variable brain abnormalities, MIM# 618443 to Neurodevelopmental disorder with or without variable brain abnormalities, OMIM:618443
Childhood onset hereditary spastic paraplegia v2.116 MAPK8IP3 Arina Puzriakova Tag Q4_21_rating tag was added to gene: MAPK8IP3.
Childhood onset hereditary spastic paraplegia v2.116 MAPK8IP3 Arina Puzriakova Classified gene: MAPK8IP3 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.116 MAPK8IP3 Arina Puzriakova Added comment: Comment on list classification: 18 individuals from 17 families reported with de novo variants in this gene (PMIDs: 30612693; 30945334) of which 8 subjects presented with spasticity, among other features. Overall there is sufficient evidence to promote this gene to Green at the next GMS panel update.
Childhood onset hereditary spastic paraplegia v2.116 MAPK8IP3 Arina Puzriakova Gene: mapk8ip3 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.97 MAPK8IP3 Arina Puzriakova Tag Q4_21_rating tag was added to gene: MAPK8IP3.
Malformations of cortical development v2.97 MAPK8IP3 Arina Puzriakova Publications for gene: MAPK8IP3 were set to 30612693
Malformations of cortical development v2.96 MAPK8IP3 Arina Puzriakova Classified gene: MAPK8IP3 as Amber List (moderate evidence)
Malformations of cortical development v2.96 MAPK8IP3 Arina Puzriakova Added comment: Comment on list classification: 18 individuals from 17 families reported with de novo variants in this gene (PMIDs: 30612693; 30945334). Various brain malformations affecting both cerebral and cerebellar structures identified in all except four individuals. Overall there is sufficient evidence to promote this gene to Green at the next GMS panel update.
Malformations of cortical development v2.96 MAPK8IP3 Arina Puzriakova Gene: mapk8ip3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1471 MAPK8IP3 Arina Puzriakova Phenotypes for gene: MAPK8IP3 were changed from Abnormal muscle tone; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Neurodevelopmental disorder with or without variable brain abnormalities, 618443 to Neurodevelopmental disorder with or without variable brain abnormalities, OMIM:618443
Hereditary ataxia with onset in adulthood v2.128 MAPK8IP3 Arina Puzriakova Phenotypes for gene: MAPK8IP3 were changed from Intellectual Disability with variable brain anomalies; Neurodevelopmental disorder with or without variable brain abnormalities, 618443 to Neurodevelopmental disorder with or without variable brain abnormalities, OMIM:618443
Malformations of cortical development v2.95 MAPK8IP3 Arina Puzriakova Phenotypes for gene: MAPK8IP3 were changed from Neurodevelopmental disorder with or without variable brain abnormalities OMIM# 605431 to Neurodevelopmental disorder with or without variable brain abnormalities, OMIM:618443
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.32 CAPN3 Dmitrijs Rots reviewed gene: CAPN3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32896923; Phenotypes: limb girdle muscle dystrophy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Distal myopathies v1.38 SMPX Dmitrijs Rots gene: SMPX was added
gene: SMPX was added to Distal myopathies. Sources: Literature
Mode of inheritance for gene: SMPX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SMPX were set to PMID: 33974137
Phenotypes for gene: SMPX were set to Distal myopathy
Penetrance for gene: SMPX were set to unknown
Mode of pathogenicity for gene: SMPX 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: SMPX was set to GREEN
Added comment: Hemizygous variants in 10 patients from 9 families with functional data.
Sources: Literature
Congenital myopathy v2.68 ACTN2 Dmitrijs Rots reviewed gene: ACTN2: Rating: ; Mode of pathogenicity: None; Publications: PMID: 34471957; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.32 ACTN2 Dmitrijs Rots gene: ACTN2 was added
gene: ACTN2 was added to Limb girdle muscular dystrophy. Sources: Literature
Mode of inheritance for gene: ACTN2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ACTN2 were set to PMID: 34471957; 30701273; 30900782
Phenotypes for gene: ACTN2 were set to Muscular dystrophy; hyperCKemia
Penetrance for gene: ACTN2 were set to unknown
Review for gene: ACTN2 was set to GREEN
Added comment: Multiple individuals from multiple families reported suggesting ACTN2 as both, monoallelic and biallelic cause of muscular dysctrophy.
Sources: Literature
Erythropoietic protoporphyria, mild variant v1.2 CLPX Aleš Maver gene: CLPX was added
gene: CLPX was added to Erythropoietic protoporphyria, mild variant. Sources: Other
Mode of inheritance for gene: CLPX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CLPX were set to 28874591
Penetrance for gene: CLPX were set to unknown
Mode of pathogenicity for gene: CLPX was set to Other
Review for gene: CLPX was set to RED
Added comment: Entry is based on a single report (PMID: 28874591) of a novel missense variant in CPLX gene (p.Gly298Asp) in a family with erythropoietic protoporphyria. The mutation is reported to occur in the ATPase active site of human CLPX, p.Gly298Asp, and it stated by authors that it results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX).Three heterozygous members of the family are reported - the proband is affected, while the two relatives have been reported to have free and zinc-PPIX accumulation in erythrocytes and associated mild photosensitivity, but are without the complete clinical symptoms of EPP.
Sources: Other
Familial chylomicronaemia syndrome (FCS) v1.19 APOB Sarah Leigh reviewed gene: APOB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v2.202 APOB Sarah Leigh edited their review of gene: APOB: Added comment: The mode of inheritance for APOB should be both monoallelic and biallelic, as Hypercholesterolemia, familial, 2 OMIM:144010 is monoallelic and Hypobetalipoproteinemia OMIM:615558 is biallelic.; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.500 APOB Sarah Leigh edited their review of gene: APOB: Added comment: The mode of inheritance for APOB should be both monoallelic and biallelic, as Hypercholesterolemia, familial, 2 OMIM:144010 is monoallelic and Hypobetalipoproteinemia OMIM:615558 is biallelic.; Changed rating: GREEN; Changed mode of pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare genetic inflammatory skin disorders v1.45 ECM1 Eleanor Williams Classified gene: ECM1 as Amber List (moderate evidence)
Rare genetic inflammatory skin disorders v1.45 ECM1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, with a recommendation for a GREEN rating following GMS review. More than 3 cases reported with a plausible disease causing variant in the ECM1 gene and a Lipoid proteinosis phenotype.
Rare genetic inflammatory skin disorders v1.45 ECM1 Eleanor Williams Gene: ecm1 has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v1.44 ECM1 Eleanor Williams Phenotypes for gene: ECM1 were changed from Urbach-Wiethe disease to Urbach-Wiethe disease, OMIM:247100; lipoid proteinosis, MONDO:0009530
Rare genetic inflammatory skin disorders v1.43 ECM1 Eleanor Williams Publications for gene: ECM1 were set to 11929856
Rare genetic inflammatory skin disorders v1.42 ECM1 Eleanor Williams Tag Q4_21_rating tag was added to gene: ECM1.
Tag Q4_21_NHS_review tag was added to gene: ECM1.
Rare genetic inflammatory skin disorders v1.42 ECM1 Eleanor Williams reviewed gene: ECM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11929856, 28720532, 33159951; Phenotypes: Urbach-Wiethe disease, OMIM:247100, lipoid proteinosis, MONDO:0009530; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.500 APOB Sarah Leigh Tag Q4_21_MOI tag was added to gene: APOB.
Undiagnosed metabolic disorders v1.500 APOB Sarah Leigh Phenotypes for gene: APOB were changed from Hypercholesterolemia, familial, 2 144010; Hypobetalipoproteinemia 615558 to Hypercholesterolemia, familial, 2 OMIM:144010; hypercholesterolemia, autosomal dominant, type B MONDO:0007751; Hypobetalipoproteinemia OMIM:615558; familial hypobetalipoproteinemia 1 MONDO:0014252
Likely inborn error of metabolism v2.202 APOB Sarah Leigh Phenotypes for gene: APOB were changed from Hypercholesterolemia, familial, 2 144010; Hypobetalipoproteinemia 615558 to Hypercholesterolemia, familial, 2 OMIM:144010; hypercholesterolemia, autosomal dominant, type B MONDO:0007751; Hypobetalipoproteinemia OMIM:615558; familial hypobetalipoproteinemia 1 MONDO:0014252
Likely inborn error of metabolism v2.201 APOB Sarah Leigh Tag Q4_21_MOI tag was added to gene: APOB.
Mosaic skin disorders - deep sequencing v1.18 PORCN Eleanor Williams Tag Q4_21_NHS_review tag was added to gene: PORCN.
Mosaic skin disorders - deep sequencing v1.18 PTPN11 Eleanor Williams Tag Q4_21_NHS_review tag was added to gene: PTPN11.
Mosaic skin disorders - deep sequencing v1.18 BRAF Eleanor Williams Tag Q4_21_NHS_review tag was added to gene: BRAF.
Multiple monogenic benign skin tumours v1.18 NOTCH3 Eleanor Williams Tag Q4_21_expert_review tag was added to gene: NOTCH3.
Tag Q4_21_NHS_review tag was added to gene: NOTCH3.
Multiple monogenic benign skin tumours v1.18 NOTCH3 Eleanor Williams changed review comment from: Comment on list classification: Promoting from grey to amber. 1 case plus functional studies supporting the role of the reported NOTCH3 variant in disease.; to: Comment on list classification: Promoting from grey to amber. 1 case plus functional studies supporting the role of the reported NOTCH3 variant in disease. Note the eligibility criteria for the clinical indication will need to be expanded before promoting to green.
Multiple monogenic benign skin tumours v1.18 PDGFRB Eleanor Williams Classified gene: PDGFRB as Amber List (moderate evidence)
Multiple monogenic benign skin tumours v1.18 PDGFRB Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey (curator removed) to amber, with a green rating recommendation if approved by the GMS. Note the eligibility criteria for the clinical indication will need to be expanded before promoting to green.
Multiple monogenic benign skin tumours v1.18 PDGFRB Eleanor Williams Gene: pdgfrb has been classified as Amber List (Moderate Evidence).
Multiple monogenic benign skin tumours v1.17 PDGFRB Eleanor Williams Tag curated_removed was removed from gene: PDGFRB.
Multiple monogenic benign skin tumours v1.17 PDGFRB Eleanor Williams Phenotypes for gene: PDGFRB were changed from Infantile myofibromatosis to Myofibromatosis, infantile, 1, OMIM:228550; myofibromatosis, infantile, 1, MONDO:0009227
Multiple monogenic benign skin tumours v1.16 PDGFRB Eleanor Williams Publications for gene: PDGFRB were set to
Multiple monogenic benign skin tumours v1.15 PDGFRB Eleanor Williams Tag Q4_21_expert_review tag was added to gene: PDGFRB.
Tag Q4_21_rating tag was added to gene: PDGFRB.
Tag Q4_21_phenotype tag was added to gene: PDGFRB.
Tag Q4_21_NHS_review tag was added to gene: PDGFRB.
Multiple monogenic benign skin tumours v1.15 PDGFRB Eleanor Williams commented on gene: PDGFRB
Structural eye disease v1.93 NDUFB11 Ivone Leong Mode of inheritance for gene: NDUFB11 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)
Pigmentary skin disorders v1.24 HCCS Ivone Leong Classified gene: HCCS as Amber List (moderate evidence)
Pigmentary skin disorders v1.24 HCCS Ivone Leong Added comment: Comment on list classification: New gene added by Tom Cullup (Great Ormond Street Hospital). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (confirmed). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Pigmentary skin disorders v1.24 HCCS Ivone Leong Gene: hccs has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v1.23 HCCS Ivone Leong Tag Q4_21_rating tag was added to gene: HCCS.
COVID-19 research v1.90 FLNA Sarah Leigh gene: FLNA was added
gene: FLNA was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: FLNA was set to Unknown
Publications for gene: FLNA were set to DOI:10.3390/genes12111842
Review for gene: FLNA was set to AMBER
Added comment: DOI: 10.3390/genes12111842 reports: Results based on DSC and SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction.
Sources: Literature
COVID-19 research v1.89 MUC5AC Sarah Leigh Publications for gene: MUC5AC were set to 10.3390/genes12111842
COVID-19 research v1.88 ABCA7 Sarah Leigh gene: ABCA7 was added
gene: ABCA7 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ABCA7 was set to Unknown
Publications for gene: ABCA7 were set to DOI:10.3390/genes12111842
Review for gene: ABCA7 was set to AMBER
Added comment: DOI: 10.3390/genes12111842 reports: Results based on DSC and SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction.
Sources: Literature
COVID-19 research v1.87 MUC5AC Sarah Leigh gene: MUC5AC was added
gene: MUC5AC was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MUC5AC was set to Unknown
Publications for gene: MUC5AC were set to 10.3390/genes12111842
Review for gene: MUC5AC was set to AMBER
Added comment: DOI: 10.3390/genes12111842 reports: Results based on DSC and SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction.
Sources: Literature
Multiple monogenic benign skin tumours v1.15 NOTCH3 Eleanor Williams Classified gene: NOTCH3 as Amber List (moderate evidence)
Multiple monogenic benign skin tumours v1.15 NOTCH3 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 1 case plus functional studies supporting the role of the reported NOTCH3 variant in disease.
Multiple monogenic benign skin tumours v1.15 NOTCH3 Eleanor Williams Gene: notch3 has been classified as Amber List (Moderate Evidence).
Multiple monogenic benign skin tumours v1.14 NOTCH3 Eleanor Williams Phenotypes for gene: NOTCH3 were changed from MYOFIBROMATOSIS, INFANTILE, 2 to ?Myofibromatosis, infantile 2, OMIM:615293; myofibromatosis, infantile, 2, MONDO:0014122
Multiple monogenic benign skin tumours v1.13 NOTCH3 Eleanor Williams Publications for gene: NOTCH3 were set to 23731542
Multiple monogenic benign skin tumours v1.12 NOTCH3 Eleanor Williams changed review comment from: Provisionally associated with ?Myofibromatosis, infantile 2 #615293 (AD) in OMIM which they state is characterized by the development of benign tumors in the skin, muscle, bone, and viscera.

PMID: 23731542 - Martignetti et al 2013 - In a family with Infantile myofibromatosis exome sequencing identified a heterozygous variant in NOTCH along with another candidate variant. By performing Sanger sequencing of 16 family members (9 affected and 7 unaffected) they found that only NOTCH3 mutation c.4556T>C (p.Leu1519Pro) segregated appropriately with affected status.; to: Provisionally associated with ?Myofibromatosis, infantile 2 #615293 (AD) in OMIM which they state is characterized by the development of benign tumors in the skin, muscle, bone, and viscera.

PMID: 23731542 - Martignetti et al 2013 - In a family with Infantile myofibromatosis exome sequencing identified a heterozygous variant in NOTCH along with another candidate variant. By performing Sanger sequencing of 16 family members (9 affected and 7 unaffected) they found that only NOTCH3 mutation c.4556T>C (p.Leu1519Pro) segregated appropriately with affected status.

PMID: 33509954 - Wu et al 2021 - looked at the molecular consequences of the NOTCH3 L1519P mutation using HEK293 cells. The NOTCH3L1519P receptor generates enhanced downstream signaling in a ligand-independent manner, but is absent from the cell surface and accumulates in the endoplasmic reticulum instead. The protein with the variant upregulates PDGFRB expression in fibroblasts. This supports a functional link between Notch and PDGF dysregulation in Infantile myofibromatosis.
Multiple monogenic benign skin tumours v1.12 NOTCH3 Eleanor Williams edited their review of gene: NOTCH3: Changed publications to: 33509954, 23731542
Multiple monogenic benign skin tumours v1.12 NOTCH3 Eleanor Williams commented on gene: NOTCH3
Mosaic skin disorders - deep sequencing v1.18 PTPN11 Eleanor Williams Classified gene: PTPN11 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v1.18 PTPN11 Eleanor Williams Added comment: Comment on list classification: Leaving rating as amber, but with recommendation for green rating after GMS confirmation given the green review from NHS reviewer.
Mosaic skin disorders - deep sequencing v1.18 PTPN11 Eleanor Williams Gene: ptpn11 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v1.17 PTPN11 Eleanor Williams Phenotypes for gene: PTPN11 were changed from Noonan syndrome; Noonan syndrome with lentigines (LEOPARD); Phakomatosis pigmentovascularis (PPV), Noonan syndrome with lentigines (LEOPARD)(151100); Speckled lentiginous naevus syndrome (deletion) to Phakomatosis pigmentovascularis (PPV), MONDO:0017318; LEOPARD syndrome 1, OMIM:151100; Speckled lentiginous naevus syndrome (deletion)
Mosaic skin disorders - deep sequencing v1.16 PTPN11 Eleanor Williams Tag Q4_21_rating tag was added to gene: PTPN11.
Mosaic skin disorders - deep sequencing v1.16 PTPN11 Eleanor Williams Phenotypes for gene: PTPN11 were changed from Noonan syndrome; Noonan syndrome with lentigines (LEOPARD) to Noonan syndrome; Noonan syndrome with lentigines (LEOPARD); Phakomatosis pigmentovascularis (PPV), Noonan syndrome with lentigines (LEOPARD)(151100); Speckled lentiginous naevus syndrome (deletion)
Mosaic skin disorders - deep sequencing v1.15 PORCN Eleanor Williams Tag mosaicism tag was added to gene: PORCN.
Mosaic skin disorders - deep sequencing v1.15 PORCN Eleanor Williams Classified gene: PORCN as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v1.15 PORCN Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for a GREEN rating following GMS review.
Mosaic skin disorders - deep sequencing v1.15 PORCN Eleanor Williams Gene: porcn has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v1.14 PORCN Eleanor Williams Tag Q4_21_rating tag was added to gene: PORCN.
Mosaic skin disorders - deep sequencing v1.14 PORCN Eleanor Williams Phenotypes for gene: PORCN were changed from Focal dermal hypoplasia (https://omim.org/entry/305600) to Focal dermal hypoplasia, OMIM:305600; focal dermal hypoplasia, MONDO:0010592
Mosaic skin disorders - deep sequencing v1.13 PORCN Eleanor Williams Publications for gene: PORCN were set to 17546030
Mosaic skin disorders - deep sequencing v1.12 PORCN Eleanor Williams edited their review of gene: PORCN: 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)
Childhood onset hereditary spastic paraplegia v2.115 IFIH1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: IFIH1.
Childhood onset hereditary spastic paraplegia v2.115 IFIH1 Arina Puzriakova Classified gene: IFIH1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.115 IFIH1 Arina Puzriakova Added comment: Comment on list classification: Spasticity can be a prominent feature of Aicardi-Goutières syndrome (OMIM:615846) and has been reported as an early presenting sign in some cases. There has also been a case of spastic paraplegia without other common manifestations such as abnormal brain imaging and impaired cognitive development.

Overall there is value in including IFIH1 on this panel and therefore this gene should be promoted to Green at the next GMS panel update.
Childhood onset hereditary spastic paraplegia v2.115 IFIH1 Arina Puzriakova Gene: ifih1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.114 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Aicardi-Goutieres syndrome 7 MIM#615846 to Aicardi-Goutieres syndrome 7, OMIM:615846
Skeletal dysplasia v2.157 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Singleton-Merten syndrome 1, 182250 to Singleton-Merten syndrome 1, OMIM:182250
Early onset or syndromic epilepsy v2.474 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Aicardi-Goutieres syndrome 7, 615846; seizures to Aicardi-Goutieres syndrome 7, OMIM:615846
Fetal anomalies v1.816 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from AICARDI-GOUTIERES SYNDROME 7; SINGLETON-MERTEN SYNDROME; Aicardi-Goutieres syndrome 7, 615846; Singleton-Merten syndrome 1, 182250 to Aicardi-Goutieres syndrome 7, OMIM:615846; Singleton-Merten syndrome 1, OMIM:182250
Mosaic skin disorders - deep sequencing v1.12 PORCN Eleanor Williams reviewed gene: PORCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 17546030, 19309688; Phenotypes: Focal dermal hypoplasia, OMIM:305600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1470 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from AICARDI-GOUTIERES SYNDROME 7 to Aicardi-Goutieres syndrome 7, OMIM:615846
Childhood onset dystonia, chorea or related movement disorder v1.203 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Aicardi-Goutieres syndrome 7 615846 to Aicardi-Goutieres syndrome 7, OMIM:615846
Adult onset dystonia, chorea or related movement disorder v1.159 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Aicardi-Goutieres syndrome 7 615846 to Aicardi-Goutieres syndrome 7, OMIM:615846
Inherited white matter disorders v1.149 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Aicardi-Goutieres Syndrome; Aicardi-Goutieres syndrome 7; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Aicardi-Goutieres syndrome 7, OMIM:615846
Intracerebral calcification disorders v1.33 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Aicardi-Goutieres syndrome 7, 615846; Aicardi-Goutières, isolated spasticity, bilateral striatal necrosis to Aicardi-Goutieres syndrome 7, OMIM:615846
Structural basal ganglia disorders v1.26 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Aicardi-Goutieres syndrome 7 615846 to Aicardi-Goutieres syndrome 7, OMIM:615846
White matter disorders and cerebral calcification - narrow panel v1.219 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Aicardi-Goutieres Syndrome; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Aicardi-Goutieres syndrome 7, 615846; Aicardi-Goutieres syndrome 7; Aicardi-Gouti res, isolated spasticity, bilateral striatal necrosis to Aicardi-Goutieres syndrome 7, OMIM:615846
COVID-19 research v1.86 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Rhinovirus and other RNA viruses (AR); Classical AGS, SLE, SP, SMS; Autoinflammatory Disorders; Aicardi-Goutieres syndrome 7 (AD); susceptibility to RNA viruses; Recurrent and prolonged infections; Defects in Intrinsic and Innate Immunity to Aicardi-Goutieres syndrome 7, OMIM:615846 (AD); Singleton-Merten syndrome 1, OMIM:182250 (AD); Susceptibility to RNA viruses (AR)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.497 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Aicardi-Goutieres syndrome 7 (AD); Classical AGS, SLE, SP, SMS; Autoinflammatory Disorders; Rhinovirus and other RNA viruses (AR); susceptibility to RNA viruses; Defects in Intrinsic and Innate Immunity to Aicardi-Goutieres syndrome 7, OMIM:615846 (AD); Singleton-Merten syndrome 1, OMIM:182250 (AD); Susceptibility to RNA viruses (AR)
Arthrogryposis v3.145 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from Multiple mitochondrial dysfunctions syndrome 3 615330 to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330
Inherited white matter disorders v1.148 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from Multiple mitochondrial dysfunctions syndrome 3, 615330 to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330
Intellectual disability v3.1469 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from Multiple mitochondrial dysfunctions syndrome 3, 615330; intellectual disability, seizures, loss of milestones to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330
Pyruvate dehydrogenase (PDH) deficiency v1.31 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 3 OMIM:615330; multiple mitochondrial dysfunctions syndrome 3 MONDO:0014132 to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330
White matter disorders and cerebral calcification - narrow panel v1.218 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from Multiple mitochondrial dysfunctions syndrome 3, 615330 to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330
Mitochondrial disorders v2.63 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Multiple mitochondrial dysfunctions syndrome 3, 615330; ?Spastic paraplegia 74, autosomal recessive to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330; ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Likely inborn error of metabolism v2.201 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Multiple mitochondrial dysfunctions syndrome 3, 615330; ?Spastic paraplegia 74, autosomal recessive to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330; ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Possible mitochondrial disorder - nuclear genes v1.60 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 3, 615330 to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330; ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Undiagnosed metabolic disorders v1.499 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Multiple mitochondrial dysfunctions syndrome 3, 615330; ?Spastic paraplegia 74, autosomal recessive to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330; ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Childhood onset hereditary spastic paraplegia v2.113 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Spastic paraplegia 74, autosomal recessive, 616451 to ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Adult onset neurodegenerative disorder v2.255 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Spastic paraplegia 74, autosomal recessive, 616451 to ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Adult onset hereditary spastic paraplegia v1.87 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Spastic paraplegia 74, autosomal recessive, 616451 to ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Hereditary spastic paraplegia v1.274 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Spastic paraplegia 74, autosomal recessive, 616451 to ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Childhood onset hereditary spastic paraplegia v2.112 IBA57 Arina Puzriakova changed review comment from: Comment on list classification: No further evidence was emerged since initial curation and clinical review in 2019 and therefore will maintain the Amber gene rating on spasticity panels at this time.; to: Comment on list classification: No further evidence has emerged since initial curation and clinical review in 2019 and therefore will maintain the Amber gene rating on spasticity panels at this time.
Childhood onset hereditary spastic paraplegia v2.112 IBA57 Arina Puzriakova Classified gene: IBA57 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.112 IBA57 Arina Puzriakova Added comment: Comment on list classification: No further evidence was emerged since initial curation and clinical review in 2019 and therefore will maintain the Amber gene rating on spasticity panels at this time.
Childhood onset hereditary spastic paraplegia v2.112 IBA57 Arina Puzriakova Gene: iba57 has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v1.59 PHKB Sarah Leigh edited their review of gene: PHKB: Added comment: Although pathogenic variants in PHKB result in reduced levels of phosphorylase kinase in the liver and muscle, it would appear that this results in hepatomegaly and minimal effect on the muscles (PMID 9215682 & 30397902).; Changed rating: RED
Rhabdomyolysis and metabolic muscle disorders v1.59 PHKB Sarah Leigh Publications for gene: PHKB were set to 27604308; 9215682; 30397902
Rhabdomyolysis and metabolic muscle disorders v1.58 PHKB Sarah Leigh Tag Q4_21_rating tag was added to gene: PHKB.
Tag Q4_21_phenotype tag was added to gene: PHKB.
Rhabdomyolysis and metabolic muscle disorders v1.58 PHKB Sarah Leigh Publications for gene: PHKB were set to 27604308
Mosaic skin disorders - deep sequencing v1.12 BRAF Eleanor Williams Classified gene: BRAF as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v1.12 BRAF Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber but with a recommendation for GREEN rating following GMS review. More than 3 cases with tissue specific mosaic missense variants reported and a relevant skin phenotype.
Mosaic skin disorders - deep sequencing v1.12 BRAF Eleanor Williams Gene: braf has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v1.11 BRAF Eleanor Williams Phenotypes for gene: BRAF were changed from Melanocytic naevus syndrome (MIM 137550); Vascular malformations; Noonan syndrome 7 (MIM 613706); LEOPARD syndrome 3 (MIM 613707); Cardio-facio-cutaneous syndrome 1 (MIM 115150) to Melanocytic naevus syndrome, OMIM:137550; Vascular malformations; Noonan syndrome 7 (MIM 613706); LEOPARD syndrome 3 , OMIM:613707; Cardio-facio-cutaneous syndrome 1, OMIM:115150
Mosaic skin disorders - deep sequencing v1.10 BRAF Eleanor Williams Publications for gene: BRAF were set to PMID: 31111470; 31891627; 29461977
Mosaic skin disorders - deep sequencing v1.9 BRAF Eleanor Williams Tag Q4_21_rating tag was added to gene: BRAF.
Mosaic skin disorders - deep sequencing v1.9 BRAF Eleanor Williams commented on gene: BRAF
Severe microcephaly v2.274 GPT2 Arina Puzriakova Classified gene: GPT2 as Amber List (moderate evidence)
Severe microcephaly v2.274 GPT2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at then next GMS panel update.
Severe microcephaly v2.274 GPT2 Arina Puzriakova Gene: gpt2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.273 GPT2 Arina Puzriakova gene: GPT2 was added
gene: GPT2 was added to Severe microcephaly. Sources: Literature
Q4_21_rating tags were added to gene: GPT2.
Mode of inheritance for gene: GPT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPT2 were set to 25758935; 27601654; 29226631; 29882329; 31471722
Phenotypes for gene: GPT2 were set to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281
Review for gene: GPT2 was set to GREEN
Added comment: Microcephaly is a prominent features of the neurodevelopmental disorder associated with biallelic variants in the GPT2 gene. Mostly all patients are to some degree microcephalic but at least 6 unrelated families (out of 11 total) have been reported with microcephaly of relevant severity to this panel (≥ -3SD). This gene is associated with a relevant phenotype in OMIM (OMIM:616281) but is not yet listed in G2P.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.111 GPT2 Arina Puzriakova Publications for gene: GPT2 were set to 29882329; 31471722; 27601654
Childhood onset hereditary spastic paraplegia v2.110 GPT2 Arina Puzriakova Tag Q4_21_rating tag was added to gene: GPT2.
Childhood onset hereditary spastic paraplegia v2.110 GPT2 Arina Puzriakova Classified gene: GPT2 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.110 GPT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel update. Spastic paraplegia is a frequently reported sign which develops later in the course of disease but is often severe. As this is a prominent feature of the condition there is value in including GPT2 on this panel. This gene is associated with a relevant phenotype in OMIM (OMIM:616281) but is not yet listed in G2P.
Childhood onset hereditary spastic paraplegia v2.110 GPT2 Arina Puzriakova Gene: gpt2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1468 GPT2 Arina Puzriakova Phenotypes for gene: GPT2 were changed from Microcephaly; Mental retardation, autosomal recessive 49, 138210; Intellectual disability; Progressive spasticity to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281
Childhood onset hereditary spastic paraplegia v2.109 GPT2 Arina Puzriakova Phenotypes for gene: GPT2 were changed from Mental retardation, autosomal recessive 49 MIM#616281 to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281
Skeletal dysplasia v2.156 PRKG2 Eleanor Williams Phenotypes for gene: PRKG2 were changed from Acromesomelic dysplasia to acromesomelic dysplasia, MONDO:0019696; spondylometaphyseal dysplasia, MONDO:0016763
Skeletal dysplasia v2.155 PRKG2 Eleanor Williams Publications for gene: PRKG2 were set to 33106379
Childhood onset hereditary spastic paraplegia v2.108 EXOSC3 Arina Puzriakova Classified gene: EXOSC3 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.108 EXOSC3 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as only two families have been reported to date with early-onset spastic paraplegia associated with biallelic variants in this gene. Other features included variable cognitive impairment and cerebellar atrophy but normal pons.
Childhood onset hereditary spastic paraplegia v2.108 EXOSC3 Arina Puzriakova Gene: exosc3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1467 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057; 34764295
Severe microcephaly v2.272 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057; 34764295
Severe microcephaly v2.271 ATP9A Sarah Leigh reviewed gene: ATP9A: Rating: AMBER; Mode of pathogenicity: None; Publications: 27626380; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1466 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 1 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Childhood onset dystonia, chorea or related movement disorder v1.202 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Hereditary ataxia with onset in adulthood v2.127 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar hypoplasia type 1B, 614678; Pontocerebellar hypoplasia, type 1B, 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Early onset or syndromic epilepsy v2.473 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar hypoplasia, type 1B, 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Fetal anomalies v1.815 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 1 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Adult onset neurodegenerative disorder v2.254 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar hypoplasia, type 1B, 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Cerebellar hypoplasia v1.61 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar Hypoplasia type 1B; Pontocerebellar Hypoplasia; Pontocerebellar hypoplasia, type 1B, 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Arthrogryposis v3.144 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar hypoplasia, type 1B 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Hereditary ataxia v1.280 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar hypoplasia, type 1B, 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Ataxia and cerebellar anomalies - narrow panel v2.276 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar Hypoplasia; Pontocerebellar hypoplasia, type 1B, 614678; Pontocerebellar Hypoplasia type 1B to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Intellectual disability v3.1465 ATP9A Sarah Leigh edited their review of gene: ATP9A: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least four variants reported in four unrelated families with a neurodevelopmental disorder (PMIDs: 34379057, 34764295). Model Atp9a−/− mice had neurobehavioural disabilities reminiscent to the behavioral patterns in the publications quoted here (PMID: 27626380).; Changed rating: GREEN; Changed publications to: 27626380
Intellectual disability v3.1465 ATP9A Sarah Leigh Classified gene: ATP9A as Amber List (moderate evidence)
Intellectual disability v3.1465 ATP9A 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 v3.1465 ATP9A Sarah Leigh Gene: atp9a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1464 ATP9A Sarah Leigh Tag Q4_21_rating tag was added to gene: ATP9A.
Primary ovarian insufficiency v1.55 C14orf39 Andrey Gagunashvili reviewed gene: C14orf39: Rating: ; Mode of pathogenicity: None; Publications: 34718620; Phenotypes: Premature ovarian failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary ovarian insufficiency v1.55 SYCE1 Andrey Gagunashvili reviewed gene: SYCE1: Rating: ; Mode of pathogenicity: None; Publications: 34718620; Phenotypes: Premature ovarian failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1464 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057
Severe microcephaly v2.271 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057
Cholestasis v1.98 MPI Ivone Leong Added comment: Comment on publications: Comment on publications: New publications added.
Cholestasis v1.98 MPI Ivone Leong Publications for gene: MPI were set to 12414827; 9585601; 10980531; 33098580; 33204592; 32905087; 32266963; 30242110
Cholestasis v1.97 MPI Ivone Leong Tag Q4_21_NHS_review tag was added to gene: MPI.
Cholestasis v1.97 LIPA Ivone Leong Added comment: Comment on publications: Comment on publications: New publications added.
Cholestasis v1.97 LIPA Ivone Leong Publications for gene: LIPA were set to 8254026; 29702543; 8617513; 7759067; 8598644; 26137452; 29731497; 23485521
Cholestasis v1.96 LIPA Ivone Leong Tag Q4_21_NHS_review tag was added to gene: LIPA.
Cholestasis v1.96 CFTR Ivone Leong changed review comment from: Comment on publications: New publicatins added.; to: Comment on publications: New publications added.
Cholestasis v1.96 CFTR Ivone Leong Added comment: Comment on publications: New publicatins added.
Cholestasis v1.96 CFTR Ivone Leong Publications for gene: CFTR were set to 21194565; 27806795; 22798282; 9934970; 26436368; 31041076
Cholestasis v1.95 CFTR Ivone Leong Publications for gene: CFTR were set to 21194565; 27806795; 22798282; 9934970
Cholestasis v1.94 CFTR Ivone Leong Tag Q4_21_NHS_review tag was added to gene: CFTR.
Cholestasis v1.94 ADK Ivone Leong Tag Q4_21_NHS_review tag was added to gene: ADK.
Cholestasis v1.94 ADK Ivone Leong Publications for gene: ADK were set to 21963049; 27500280; 26642971
White matter disorders and cerebral calcification - narrow panel v1.217 ELOVL1 Arina Puzriakova Entity copied from Hereditary spastic paraplegia - childhood onset v2.107
White matter disorders and cerebral calcification - narrow panel v1.217 ELOVL1 Arina Puzriakova gene: ELOVL1 was added
gene: ELOVL1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list,Expert Review Amber
missense, Q4_21_rating tags were added to gene: ELOVL1.
Mode of inheritance for gene: ELOVL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELOVL1 were set to 23689133; 29496980; 30487246; 32123819
Phenotypes for gene: ELOVL1 were set to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527
Ichthyosis and erythrokeratoderma v1.69 ELOVL1 Arina Puzriakova Entity copied from Hereditary spastic paraplegia - childhood onset v2.107
Ichthyosis and erythrokeratoderma v1.69 ELOVL1 Arina Puzriakova gene: ELOVL1 was added
gene: ELOVL1 was added to Ichthyosis and erythrokeratoderma. Sources: Expert list,Expert Review Amber
missense, Q4_21_rating tags were added to gene: ELOVL1.
Mode of inheritance for gene: ELOVL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELOVL1 were set to 23689133; 29496980; 30487246; 32123819
Phenotypes for gene: ELOVL1 were set to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527
Childhood onset hereditary spastic paraplegia v2.107 ELOVL1 Arina Puzriakova Publications for gene: ELOVL1 were updated from 29496980; 32123819; 30487246 to 23689133; 29496980; 30487246; 32123819
Childhood onset hereditary spastic paraplegia v2.106 ELOVL1 Arina Puzriakova Classified gene: ELOVL1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.106 ELOVL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Although only a single variant has been reported to date this was shown to arise de novo in unrelated individuals and the possibility of a founder effect was ruled out. Pathogenicity is supported by functional data including in vitro studies of the variant and complimentary animal models. Overall this is sufficient evidence to rate this gene as Green at the next GMS panel update.
Childhood onset hereditary spastic paraplegia v2.106 ELOVL1 Arina Puzriakova Gene: elovl1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.105 ELOVL1 Arina Puzriakova Tag missense tag was added to gene: ELOVL1.
Tag Q4_21_rating tag was added to gene: ELOVL1.
Childhood onset hereditary spastic paraplegia v2.105 ELOVL1 Arina Puzriakova reviewed gene: ELOVL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23689133, 29496980, 30487246, 32123819; Phenotypes: Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.236 ELOVL1 Arina Puzriakova Mode of inheritance for gene: ELOVL1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v2.235 ELOVL1 Arina Puzriakova Phenotypes for gene: ELOVL1 were changed from to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527
Childhood onset hereditary spastic paraplegia v2.105 ELOVL1 Arina Puzriakova Phenotypes for gene: ELOVL1 were changed from Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, MIM# 618527 to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527
Adult onset hereditary spastic paraplegia v1.86 CPT1C Arina Puzriakova Classified gene: CPT1C as Amber List (moderate evidence)
Adult onset hereditary spastic paraplegia v1.86 CPT1C Arina Puzriakova Added comment: Comment on list classification: Overall one family with confirmed adult-onset and one with childhood-onset have been reported, as well as two further unrelated cases but unfortunately without indication of age of onset. Although onset is variable, the gene-disease relationship is supported by a strong animal model, and therefore it is worth including CPT1C on both HSP panels as Green.
Adult onset hereditary spastic paraplegia v1.86 CPT1C Arina Puzriakova Gene: cpt1c has been classified as Amber List (Moderate Evidence).
Adult onset hereditary spastic paraplegia v1.85 CPT1C Arina Puzriakova Tag Q4_21_rating tag was added to gene: CPT1C.
Childhood onset hereditary spastic paraplegia v2.104 CPT1C Arina Puzriakova Classified gene: CPT1C as Green List (high evidence)
Childhood onset hereditary spastic paraplegia v2.104 CPT1C Arina Puzriakova Added comment: Comment on list classification: Overall one family with confirmed adult-onset and one with childhood-onset have been reported, as well as two further unrelated cases but unfortunately without indication of age of onset. Although onset is variable, the gene-disease relationship is supported by a strong animal model, and therefore it is worth including CPT1C on both HSP panels as Green.
Childhood onset hereditary spastic paraplegia v2.104 CPT1C Arina Puzriakova Gene: cpt1c has been classified as Green List (High Evidence).
Childhood onset hereditary spastic paraplegia v2.103 CPT1C Arina Puzriakova Publications for gene: CPT1C were set to 25751282; 30564185
Childhood onset hereditary spastic paraplegia v2.102 CPT1C Arina Puzriakova reviewed gene: CPT1C: Rating: ; Mode of pathogenicity: None; Publications: 30911584; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pigmentary skin disorders v1.23 HCCS Ivone Leong Tag Q4_21_rating was removed from gene: HCCS.
Pigmentary skin disorders v1.23 HCCS Ivone Leong Tag Q4_21_rating tag was added to gene: HCCS.
Tag Q4_21_NHS_review tag was added to gene: HCCS.
Pigmentary skin disorders v1.23 HCCS Ivone Leong Phenotypes for gene: HCCS were changed from Linear Skin Defects with Multiple Congenital Anomalies to Linear skin defects with multiple congenital anomalies 1, OMIM:309801
Intellectual disability v3.1463 HCCS Ivone Leong Tag Q4_21_MOI tag was added to gene: HCCS.
Intellectual disability v3.1463 HCCS Ivone Leong reviewed gene: HCCS: Rating: ; 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)
Adult onset hereditary spastic paraplegia v1.85 CPT1C Arina Puzriakova Phenotypes for gene: CPT1C were changed from ?Spastic paraplegia 73, autosomal dominant, 616282 to Spastic paraplegia 73, autosomal dominant, OMIM:616282
Childhood onset hereditary spastic paraplegia v2.102 CPT1C Arina Puzriakova Phenotypes for gene: CPT1C were changed from ?Spastic paraplegia 73, autosomal dominant, 616282, AD to Spastic paraplegia 73, autosomal dominant, OMIM:616282
Childhood onset hereditary spastic paraplegia v2.101 AP5Z1 Arina Puzriakova Publications for gene: AP5Z1 were set to Slabicki et al. (2010); 20613862; 24833714; 27606357
Childhood onset hereditary spastic paraplegia v2.100 AP5Z1 Arina Puzriakova reviewed gene: AP5Z1: Rating: ; Mode of pathogenicity: None; Publications: 24833714, 27606357, 33543803; Phenotypes: Spastic paraplegia 48, autosomal recessive, OMIM:613647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v1.22 DDX3X Ivone Leong Tag Q4_21_rating tag was added to gene: DDX3X.
Pigmentary skin disorders v1.22 DDX3X Ivone Leong Tag Q4_21_NHS_review tag was added to gene: DDX3X.
Pigmentary skin disorders v1.22 DDX3X Ivone Leong Classified gene: DDX3X as Amber List (moderate evidence)
Pigmentary skin disorders v1.22 DDX3X Ivone Leong Added comment: Comment on list classification: New gene added by Tom Cullup (Great Ormond Street Hospital). This gene is associated with a phenotype in OMIM and Gene2Phenotype (confirmed). There is enough evidence to support a gene-disease association. It should be noted that not all patient develops skin pigmentation anomalies; however, there are >3 unrelated cases. This gene should be rated Green at the next review.
Pigmentary skin disorders v1.22 DDX3X Ivone Leong Gene: ddx3x has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1463 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic paraplegia 48, autosomal recessive 613647 to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Childhood onset hereditary spastic paraplegia v2.100 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic paraplegia 48, autosomal recessive, OMIM:613647 to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Pigmentary skin disorders v1.21 DDX3X Ivone Leong Phenotypes for gene: DDX3X were changed from INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, SNIJDERS BLOK TYPE to Intellectual developmental disorder, X-linked, syndrome, Snijders Blok type, OMIM:300958
Childhood onset hereditary spastic paraplegia v2.99 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic Paraplegia, Recessive; Spastic paraplegia 48, autosomal recessive to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Hereditary spastic paraplegia v1.273 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic Paraplegia, Recessive ; Spastic paraplegia 48, autosomal recessive to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Childhood onset dystonia, chorea or related movement disorder v1.201 HPRT1 Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: HPRT1.
Tag Q4_21_rating tag was added to gene: HPRT1.
Childhood onset dystonia, chorea or related movement disorder v1.201 HPRT1 Arina Puzriakova commented on gene: HPRT1
Childhood onset dystonia, chorea or related movement disorder v1.201 HPRT1 Arina Puzriakova Publications for gene: HPRT1 were set to
Early onset dystonia v1.98 HPRT1 Arina Puzriakova Mode of inheritance for gene: HPRT1 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Adult onset neurodegenerative disorder v2.253 HPRT1 Arina Puzriakova Mode of inheritance for gene: HPRT1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Adult onset neurodegenerative disorder v2.252 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Dystonia to Lesch-Nyhan syndrome, OMIM:300322
Early onset dystonia v1.97 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Dystonia to Lesch-Nyhan syndrome, OMIM:300322; Dystonia
Childhood onset dystonia, chorea or related movement disorder v1.200 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Lesch-Nyhan syndrome, 300322 to Lesch-Nyhan syndrome, OMIM:300322; Dystonia
Adult onset dystonia, chorea or related movement disorder v1.158 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Lesch-Nyhan syndrome, 300322; Dystonia to Lesch-Nyhan syndrome, OMIM:300322; Dystonia
Intellectual disability v3.1462 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Lesch-Nyhan syndrome, 300322HPRT-related gout, 300323; GOUT HPRT-RELATED (GOUT-HPRT) to Lesch-Nyhan syndrome, OMIM:300322
Early onset or syndromic epilepsy v2.472 HPRT1 Arina Puzriakova Mode of inheritance for gene: HPRT1 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v2.471 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from to Lesch-Nyhan syndrome, OMIM:300322
Fetal anomalies v1.814 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from LESCH-NYHAN SYNDROME; GOUT HPRT-RELATED to Hyperuricemia, HRPT-related, OMIM:300323; Lesch-Nyhan syndrome, OMIM:300322
Likely inborn error of metabolism v2.200 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from HPRT-related gout to Hyperuricemia, HRPT-related, OMIM:300323; Lesch-Nyhan syndrome, OMIM:300322
Nephrocalcinosis or nephrolithiasis v2.25 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Lesch-Nyhan syndrome, 300322 to Hyperuricemia, HRPT-related, OMIM:300323; Lesch-Nyhan syndrome, OMIM:300322
Undiagnosed metabolic disorders v1.498 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from HPRT-related gout 300323; Lesch-Nyhan syndrome 300322 to Hyperuricemia, HRPT-related, OMIM:300323; Lesch-Nyhan syndrome, OMIM:300322
Pigmentary skin disorders v1.20 COX7B Ivone Leong Classified gene: COX7B as Amber List (moderate evidence)
Pigmentary skin disorders v1.20 COX7B Ivone Leong Added comment: Comment on list classification: New gene added by Tom Cullup (Great Ormond Street Hospital). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (confirmed). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Pigmentary skin disorders v1.20 COX7B Ivone Leong Gene: cox7b has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v1.19 COX7B Ivone Leong Tag Q4_21_rating tag was added to gene: COX7B.
Tag Q4_21_NHS_review tag was added to gene: COX7B.
Structural eye disease v1.92 COX7B Ivone Leong Added comment: Comment on mode of inheritance: MOI 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)" as the latter is the correct MOI.
Structural eye disease v1.92 COX7B Ivone Leong Mode of inheritance for gene: COX7B 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)
Severe early-onset obesity v2.45 KIDINS220 Arina Puzriakova Classified gene: KIDINS220 as Amber List (moderate evidence)
Severe early-onset obesity v2.45 KIDINS220 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Severe early-onset obesity v2.45 KIDINS220 Arina Puzriakova Gene: kidins220 has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v2.44 KIDINS220 Arina Puzriakova gene: KIDINS220 was added
gene: KIDINS220 was added to Severe early-onset obesity. Sources: Literature
Q4_21_rating tags were added to gene: KIDINS220.
Mode of inheritance for gene: KIDINS220 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KIDINS220 were set to 27005418; 29667355; 33763417
Phenotypes for gene: KIDINS220 were set to Spastic paraplegia, intellectual disability, nystagmus, and obesity, OMIM:617296
Review for gene: KIDINS220 was set to GREEN
Added comment: Seven individuals from five unrelated families have been reported with spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) syndrome (OMIM:617296) associated with monoallelic variants in the KIDINS220 gene. Phenotypes include early-onset obesity and, where indicated, this translates to a weight above the 99th percentile in infancy.
Sources: Literature
Intellectual disability v3.1461 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity, 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity OMIM:617296
Intellectual disability v3.1460 KIDINS220 Arina Puzriakova Publications for gene: KIDINS220 were set to 27005418; 29667355
Adult onset hereditary spastic paraplegia v1.84 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity, autosomal dominant, 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity, OMIM:617296
Childhood onset hereditary spastic paraplegia v2.98 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity, 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity, OMIM:617296
Adult onset neurodegenerative disorder v2.251 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity, OMIM:617296
Fetal anomalies v1.813 KIDINS220 Arina Puzriakova Added comment: Comment on phenotypes: Added relevant phenotype now listed in OMIM (MIM# 619501)
Fetal anomalies v1.813 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity OMIM:617296; spastic paraplegia, intellectual disability, nystagmus, and obesity MONDO:0015007; cerebral ventriculomegaly; limb contractures to Ventriculomegaly and arthrogryposis, OMIM:619501
Hydrocephalus v2.125 KIDINS220 Arina Puzriakova Added comment: Comment on phenotypes: Added relevant phenotype now listed in OMIM (MIM# 619501)
Hydrocephalus v2.125 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from brain ventriculomegaly and limb contractures to Ventriculomegaly and arthrogryposis, OMIM:619501
Arthrogryposis v3.143 KIDINS220 Arina Puzriakova Added comment: Comment on phenotypes: Added relevant phenotype now listed in OMIM (MIM# 619501)
Arthrogryposis v3.143 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from brain ventriculomegaly and limb contractures to Ventriculomegaly and arthrogryposis, OMIM:619501
Hereditary spastic paraplegia v1.272 KIDINS220 Sarah Leigh Added comment: Comment on mode of pathogenicity: Personal communication from Dmitrijs Rots (RadboudUMC). Prompted by the occurrence of a KIDINS220 nonsense variant in the middle of the gene, in a family without spastic paraplegia (HSP) or other features; an in-depth analysis of KIDINS220 variants was performed. It would appear that KIDINS220 gene is tolerant of LOF variants (nonsense, frameshift) in gnomAD population (hence pLI~ 0, in the PanelApp review by Dmitrijs Rots (RadboudUMC), 4 Nov 2021). This was unexpected, as KIDINS220-associated-HSP presents in childhood, so it would appear that haploinsufficiency is unlikely as the mechanism. In addition, there were nonsense/frameshift HSP-associated variants in KIDINS220, but they were located in the last two exons of the gene and so likely to escape nonsense mediated decay. Therefore, it is proposed that rather a LOF mechanism a dominant negative effect may be responsible, however, further cases need to be identified to confirm this.
Hereditary spastic paraplegia v1.272 KIDINS220 Sarah Leigh Mode of pathogenicity for gene: KIDINS220 was changed from None to None
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 MARS Arina Puzriakova commented on gene: MARS
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 MARS Arina Puzriakova Tag watchlist tag was added to gene: MARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 AARS Arina Puzriakova changed review comment from: Gene was reassessed in view of the recent Green review by Alan Lehmann. An additional case is necessary to allow corroboration of this gene-disease association (added 'watchlist' tag). At present, CARS1 is the only aminoacyl tRNA synthetase gene for which sufficient evidence has been reported to warrant a Green rating on this panel.; to: Gene was reassessed in view of the recent Green review by Alan Lehmann (5 Nov 2021). An additional case is necessary to allow corroboration of this gene-disease association (added 'watchlist' tag). At present, CARS1 is the only aminoacyl tRNA synthetase gene for which sufficient evidence has been reported to warrant a Green rating on this panel.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 AARS Arina Puzriakova commented on gene: AARS
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 AARS Arina Puzriakova Tag watchlist tag was added to gene: AARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 TARS Arina Puzriakova Tag watchlist tag was added to gene: TARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 TARS Arina Puzriakova Classified gene: TARS as Amber List (moderate evidence)
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 TARS Arina Puzriakova Added comment: Comment on list classification: Adding this gene as Amber as currently only two unrelated individuals have been reported with variants and trichothiodystrophy (PMID: 31374204). Familial segregation was not reported in either case. Functional studies demonstrate the variants exert a loss-of-function effect but an additional case would help corroborate this gene-disease association (added 'watchlist' tag). At present, CARS1 is the only aminoacyl tRNA synthetase gene for which sufficient evidence has been reported to warrant a Green rating on this panel.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 TARS Arina Puzriakova Gene: tars has been classified as Amber List (Moderate Evidence).
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.24 TARS Arina Puzriakova Mode of pathogenicity for gene: TARS 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
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.23 TARS Arina Puzriakova Publications for gene: TARS were set to PMID 31374204
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.22 TARS Arina Puzriakova Phenotypes for gene: TARS were changed from Trichothiodystrophy 7, nonphotosensitive to Trichothiodystrophy 7, nonphotosensitive, OMIM:618546
DDG2P v2.53 TARS Arina Puzriakova Tag new-gene-name tag was added to gene: TARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.21 TARS Arina Puzriakova Tag new-gene-name tag was added to gene: TARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.21 CARS Arina Puzriakova Publications for gene: CARS were set to PMID 30824121
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.20 CARS Arina Puzriakova Classified gene: CARS as Amber List (moderate evidence)
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.20 CARS 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 four individuals from three unrelated families harbouring different biallelic variants in the CARS gene. Clinical presentation includes ID and brittle hair and nails, features which overlap with the trichothiodystrophy component of this panel. Some supportive functional studies included.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.20 CARS Arina Puzriakova Gene: cars has been classified as Amber List (Moderate Evidence).
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.19 CARS Arina Puzriakova Tag Q4_21_rating tag was added to gene: CARS.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.19 CARS Arina Puzriakova Tag new-gene-name tag was added to gene: CARS.
Pigmentary skin disorders v1.19 COX7B Ivone Leong Phenotypes for gene: COX7B were changed from Linear Skin Defects with Multiple Congenital Anomalies to Linear skin defects with multiple congenital anomalies 2, OMIM:300887
Intellectual disability v3.1459 CARS Arina Puzriakova Phenotypes for gene: CARS were changed from Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay; Microcephaly, developmental delay, and brittle hair syndrome MIM#618891 to Microcephaly, developmental delay, and brittle hair syndrome, OMIM:618891
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.19 CARS Arina Puzriakova Phenotypes for gene: CARS were changed from Microcephaly; Developmental Delay; Brittle Hair to Microcephaly, developmental delay, and brittle hair syndrome, OMIM:618891
Rare multisystem ciliopathy disorders v1.153 TMEM218 Ivone Leong Classified gene: TMEM218 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.153 TMEM218 Ivone Leong Gene: tmem218 has been classified as Green List (High Evidence).
Rare multisystem ciliopathy disorders v1.152 TMEM218 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is sufficient evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is sufficient evidence to support a gene-disease association. This gene has been rated Green.
Rare multisystem ciliopathy disorders v1.152 TMEM218 Ivone Leong Tag Q4_21_rating was removed from gene: TMEM218.
Tag Q4_21_NHS_review was removed from gene: TMEM218.
Ophthalmological ciliopathies v1.26 TMEM218 Ivone Leong Entity copied from Neurological ciliopathies v1.24
Ophthalmological ciliopathies v1.26 TMEM218 Ivone Leong gene: TMEM218 was added
gene: TMEM218 was added to Ophthalmological ciliopathies. Sources: Literature,Expert Review Amber
Q4_21_rating, Q4_21_NHS_review tags were added to gene: TMEM218.
Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM218 were set to 25161209; 33791682
Phenotypes for gene: TMEM218 were set to Joubert syndrome 39, OMIM:619562
Rare multisystem ciliopathy disorders v1.152 TMEM218 Ivone Leong Entity copied from Neurological ciliopathies v1.24
Rare multisystem ciliopathy disorders v1.152 TMEM218 Ivone Leong gene: TMEM218 was added
gene: TMEM218 was added to Rare multisystem ciliopathy disorders. Sources: Literature,Expert Review Amber
Q4_21_rating, Q4_21_NHS_review tags were added to gene: TMEM218.
Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM218 were set to 25161209; 33791682
Phenotypes for gene: TMEM218 were set to Joubert syndrome 39, OMIM:619562
Retinal disorders v2.234 TMEM218 Ivone Leong Entity copied from Neurological ciliopathies v1.24
Retinal disorders v2.234 TMEM218 Ivone Leong gene: TMEM218 was added
gene: TMEM218 was added to Retinal disorders. Sources: Literature,Expert Review Amber
Q4_21_rating, Q4_21_NHS_review tags were added to gene: TMEM218.
Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM218 were set to 25161209; 33791682
Phenotypes for gene: TMEM218 were set to Joubert syndrome 39, OMIM:619562
Neurological ciliopathies v1.24 TMEM218 Ivone Leong Classified gene: TMEM218 as Amber List (moderate evidence)
Neurological ciliopathies v1.24 TMEM218 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is sufficient evidence to support a gene-disease association. This gene should be rated Green at the next review.
Neurological ciliopathies v1.24 TMEM218 Ivone Leong Gene: tmem218 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v1.23 TMEM218 Ivone Leong Tag Q4_21_NHS_review tag was added to gene: TMEM218.
Neurological ciliopathies v1.23 TMEM218 Ivone Leong Tag Q4_21_rating tag was added to gene: TMEM218.
Intellectual disability v3.1458 GABRD Arina Puzriakova Classified gene: GABRD as Amber List (moderate evidence)
Intellectual disability v3.1458 GABRD Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases to rate this gene as Green at the next GMS panel update. Although all patients presented epilepsy, it is not clear from the case reports whether cognitive impairment was secondary or independent of seizures. For this reason I think its worth including GABRD on this panel as it is plausible that DD may be evident prior to seizure onset (ranging from 4 months to 4 years in report)
Intellectual disability v3.1458 GABRD Arina Puzriakova Gene: gabrd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1457 GABRD Arina Puzriakova gene: GABRD was added
gene: GABRD was added to Intellectual disability. Sources: Literature
Q4_21_rating tags were added to gene: GABRD.
Mode of inheritance for gene: GABRD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRD were set to 34633442
Phenotypes for gene: GABRD were set to {Epilepsy, idiopathic generalized, 10}, OMIM:613060; {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060
Mode of pathogenicity for gene: GABRD 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: GABRD was set to GREEN
Added comment: Ahring et al., 2021 (PMID: 34633442) reports on at least 3 unrelated individuals with de novo variants and one family with 3 affected individuals harbouring an inherited variant in the GABRD gene. All variants exerted a gain-of-function effect and all carriers displayed a homogenous phenotype of generalised epilepsy (median age of onset 10.5 months, medically refractory in 5/6) and various degrees of learning difficulties or ID (learning difficulties in 1, mild ID in 2, mild to moderate ID in 1, and severe to profound ID in 2).

NB. A further three individuals were excluded from phenotypic analysis as their variants (p.M87L and p.V442I) did not show any detectable functional changes. There was also another patient with a loss-of-function variant but they displayed ASD, normal intelligence and no seizure history.
Sources: Literature
Neurological ciliopathies v1.23 TMEM218 Ivone Leong Phenotypes for gene: TMEM218 were changed from Joubert syndrome; retinal dystrophy; polycystic kidneys; occipital encephalocele to Joubert syndrome 39, OMIM:619562
Neurological ciliopathies v1.22 TMEM218 Ivone Leong Publications for gene: TMEM218 were set to 25161209; https://doi.org/10.1016/j.xhgg.2020.100016
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Tag Q4_21_rating tag was added to gene: GABRD.
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Classified gene: GABRD as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but this gene should now be promoted to Green at the next GMS panel update.

New evidence identified by Helen Lord (OUH NHS) highlights at least 3 unrelated individuals with de novo variants and one family with 3 affected individuals harbouring an inherited variant in the GABRD gene (PMID: 34633442). All variants exerted a gain-of-function effect and all carriers displayed a homogenous phenotype of generalised epilepsy (median age of onset 10.5 months, medically refractory in 5/6) and various degrees of learning difficulties or ID.
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Gene: gabrd has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.469 GABRD Arina Puzriakova Mode of pathogenicity for gene: GABRD 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 v2.468 GABRD Arina Puzriakova Publications for gene: GABRD were set to 29785705
Early onset or syndromic epilepsy v2.467 GABRD Arina Puzriakova Phenotypes for gene: GABRD were changed from {Epilepsy, idiopathic generalized, 10} 613060; {Epilepsy, juvenile myoclonic, susceptibility to} 613060; {Epilepsy, generalized, with febrile seizures plus, type 5, susceptibility to} 613060 to {Epilepsy, idiopathic generalized, 10}, OMIM:613060; {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060; {Generalized epilepsy with febrile seizures plus, type 5, susceptibility to}, OMIM:613060
Early onset or syndromic epilepsy v2.466 GABRD Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: GABRD.
Ichthyosis and erythrokeratoderma v1.68 ASPRV1 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: ASPRV1.
Skeletal dysplasia v2.154 PRKG2 Alistair Pagnamenta reviewed gene: PRKG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34782440, 33106379, 34680883; Phenotypes: spondylometaphyseal, acromesomelic dysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited polyposis and early onset colorectal cancer - germline testing v1.26 AXIN2 Arina Puzriakova Classified gene: AXIN2 as Amber List (moderate evidence)
Inherited polyposis and early onset colorectal cancer - germline testing v1.26 AXIN2 Arina Puzriakova Gene: axin2 has been classified as Amber List (Moderate Evidence).
Inherited polyposis and early onset colorectal cancer - germline testing v1.25 AXIN2 Arina Puzriakova gene: AXIN2 was added
gene: AXIN2 was added to Inherited polyposis. Sources: Literature
Q4_21_rating tags were added to gene: AXIN2.
Mode of inheritance for gene: AXIN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AXIN2 were set to 15042511; 21416598; 30671715; 32807118; 34637023
Phenotypes for gene: AXIN2 were set to Oligodontia-colorectal cancer syndrome, OMIM:608615
Review for gene: AXIN2 was set to GREEN
Added comment: AXIN2 is associated with a relevant phenotype in OMIM (MIM# 608615) but is not yet listed in Gen2Phen. At least 6 unrelated families reported with colorectal cancer and/or colon polyps due to monoallelic variants in the AXIN2. This is often concurrent with oligodontia. Sufficient cases to rate as Green on this panel.
Sources: Literature
Ectodermal dysplasia v1.30 AXIN2 Arina Puzriakova Publications for gene: AXIN2 were set to 15042511
Ectodermal dysplasia v1.29 AXIN2 Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: AXIN2.
Ectodermal dysplasia v1.29 AXIN2 Arina Puzriakova Classified gene: AXIN2 as Amber List (moderate evidence)
Ectodermal dysplasia v1.29 AXIN2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Tom Cullup (GOSH). Variants are associated with tooth agenesis (PMID: 15042511; 21626677; 30671715; 32807118), often additionally with colon polyps and colorectal cancer. Two families have been identified with concurrent ectodermal dysplasia including sparse or brittle hair and/or eyebrows and dry skin (PMID: 21416598; 34637023).

Given that in most families ectodermal features are isolated to oligodontia only, this gene will be flagged for GMS review to determine whether there is enough evidence to rate AXIN2 as Green on this panel.
Ectodermal dysplasia v1.29 AXIN2 Arina Puzriakova Gene: axin2 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.28 AXIN2 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: AXIN2.
Cutaneous photosensitivity with a likely genetic cause v1.8 ANAPC1 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: ANAPC1.
Ectodermal dysplasia v1.28 ANAPC1 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: ANAPC1.
Ectodermal dysplasia v1.28 AXIN2 Arina Puzriakova Phenotypes for gene: AXIN2 were changed from OLIGODONTIA-COLORECTAL CANCER SYNDROME to Oligodontia-colorectal cancer syndrome, OMIM:608615
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60 AXIN2 Arina Puzriakova Mode of inheritance for gene: AXIN2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.59 AXIN2 Arina Puzriakova Phenotypes for gene: AXIN2 were changed from Oligodontia-colorectal cancer syndrome 604025 to Oligodontia-colorectal cancer syndrome, OMIM:608615
Cholestasis v1.93 MPI Miranda Durkie reviewed gene: MPI: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33413482, PMID: 28108845; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.93 LIPA Miranda Durkie reviewed gene: LIPA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26137452, PMID: 33964214; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.93 CFTR Miranda Durkie reviewed gene: CFTR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22798282, PMID: 27806795, PMID: 26436368, PMID: 31041076; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v1.93 ADK Miranda Durkie reviewed gene: ADK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33309011, PMID: 27500280, PMID: 21963049; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.466 CLPB Arina Puzriakova Publications for gene: CLPB were set to 26916670; 25597510; 25597511
Early onset or syndromic epilepsy v2.465 CLPB Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: CLPB.
Early onset or syndromic epilepsy v2.465 CLPB Arina Puzriakova reviewed gene: CLPB: Rating: ; Mode of pathogenicity: None; Publications: 25597510, 25597511, 26916670, 28687938, 34140661; Phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.199 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Childhood onset dystonia, chorea or related movement disorder v1.199 CLPB Arina Puzriakova Publications for gene: CLPB were set to
Childhood onset dystonia, chorea or related movement disorder v1.198 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with at least 7 affected individuals reported with a movement disorder. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease. Three individuals were nonambulatory and one was ambulatory but with a wide based gait and not able to run or jump. Some functional studies of heterozygous variants were performed.
Childhood onset dystonia, chorea or related movement disorder v1.198 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.812 CLPB Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: CLPB.
Tag Q4_21_MOI tag was added to gene: CLPB.
Fetal anomalies v1.812 CLPB Arina Puzriakova Publications for gene: CLPB were set to
Fetal anomalies v1.811 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease. No prenatal findings were specifically mentioned but given the otherwise comparable clinical presentations, monoallelic inheritance may also be of relevance to this panel. Therefore, will flag this for further GMS review.
Fetal anomalies v1.811 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.62 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Possible mitochondrial disorder - nuclear genes v1.59 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Mitochondrial disorders v2.62 CLPB Arina Puzriakova Publications for gene: CLPB were set to PMID: 25595726; PMID: 25597510; PMID: 25597511; PMID: 25650066
Possible mitochondrial disorder - nuclear genes v1.59 CLPB Arina Puzriakova Publications for gene: CLPB were set to
Mitochondrial disorders v2.61 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease including 3-MGA-uria in all cases. Some functional studies were performed which demonstrated changes in the mitochondrial proteome in patient fibroblasts.
Mitochondrial disorders v2.61 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.58 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease including 3-MGA-uria in all cases. Some functional studies were performed which demonstrated changes in the mitochondrial proteome in patient fibroblasts.
Possible mitochondrial disorder - nuclear genes v1.58 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.496 CLPB Arina Puzriakova changed review comment from: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than >10 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including moderate to severe congenital/early-onset neutropenia in 5/6 cases. Some functional studies of heterozygous variants were performed.; to: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than 10 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including moderate to severe congenital/early-onset neutropenia in 5/6 cases. Some functional studies of heterozygous variants were performed.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.496 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.496 CLPB Arina Puzriakova Publications for gene: CLPB were set to 27891836; 25597510; 28687938; 25597511; 25650066; 26916670
Primary immunodeficiency or monogenic inflammatory bowel disease v2.495 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than >10 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including moderate to severe congenital/early-onset neutropenia in 5/6 cases. Some functional studies of heterozygous variants were performed.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.495 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1456 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25597510
Intellectual disability v3.1455 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including mild to severe DD/ID in all cases. Some functional studies of heterozygous variants were performed.
Intellectual disability v3.1455 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1454 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Cytopenia - NOT Fanconi anaemia v1.47 CLPB Arina Puzriakova Tag Q4_21_rating tag was added to gene: CLPB.
Cytopenia - NOT Fanconi anaemia v1.47 CLPB Arina Puzriakova Classified gene: CLPB as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.47 CLPB Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but should be made Green at the next GMS panel update.

Neutropenia is often reported and can be a severe and early feature, sometimes present from birth. Neutropenia was observed in at least 11 biallelic cases and 5 monoallelic cases which is sufficient for a Green rating under the MOI 'Both mono- and biallelic'
Cytopenia - NOT Fanconi anaemia v1.47 CLPB Arina Puzriakova Gene: clpb has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.46 CLPB Arina Puzriakova Publications for gene: CLPB were set to
Cytopenia - NOT Fanconi anaemia v1.45 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.497 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI from 'Biallelic' to 'Both mono- and biallelic'.

Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, six unrelated individuals with de novo monoallelic missense variants in CLPB were identified (PMID: 34140661). The phenotype strongly overlapped with that observed in the recessive disease, including 3-MGA-uria in all cases.
Undiagnosed metabolic disorders v1.497 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.496 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25595726; 25597510; 25597511; 25650066
Likely inborn error of metabolism v2.199 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25597510; 25597511; 25650066; 25595726
Likely inborn error of metabolism v2.198 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Likely inborn error of metabolism v2.198 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype overlapped with that observed in the recessive disease including neurodevelopmental delay, seizures, 3-MGA-uria, and neutropenia. Some functional studies of heterozygous variants were performed.
Likely inborn error of metabolism v2.198 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.60 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria with the following: cataract, renal cysts and nephrocalcinosis; progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder; cataract, neutropenia, epilepsy; congenital microcephaly and severe encephalopathy to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Childhood onset dystonia, chorea or related movement disorder v1.197 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Early onset or syndromic epilepsy v2.465 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from Seizures; Generalised epilepsy; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Fetal anomalies v1.810 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-METHYLGLUTACONIC ACIDURIA, TYPE VII, WITH CATARACTS, NEUROLOGIC INVOLVEMENT AND NEUTROPENIA to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Possible mitochondrial disorder - nuclear genes v1.57 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Primary immunodeficiency or monogenic inflammatory bowel disease v2.494 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271; 3-methylglutaconic aciduria, type 7; Recurrent or severe infection; Neurocognitive developmental aberrations, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR; Congenital defects of phagocyte number or function to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Undiagnosed metabolic disorders v1.495 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria with the following: cataract, renal cysts and nephrocalcinosis; progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder; cataract, neutropenia, epilepsy; congenital microcephaly and severe encephalopathy to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Likely inborn error of metabolism v2.197 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria with the following: cataract, renal cysts and nephrocalcinosis; cataract, neutropenia, epilepsy; congenital microcephaly and severe encephalopathy; progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Cytopenia - NOT Fanconi anaemia v1.44 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Primary immunodeficiency or monogenic inflammatory bowel disease v2.493 IKZF3 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Upgraded from Red to Amber but there is now enough evidence to promote this gene to Green at the next GMS panel update. Two unrelated families displaying comparable immunologic disorders including T and B cell abnormalities with recurrent infections (PMID: 34155405; 34694366). Strong functional support including animal model and in vitro studies.; to: Comment on list classification: Upgraded from Red to Amber but there is now enough evidence to promote this gene to Green at the next GMS panel update. Two unrelated families displaying comparable immunologic disorders including T and B cell abnormalities with recurrent infections (PMID: 34155405; 34694366). Strong functional support including animal model and in vitro studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.493 IKZF3 Arina Puzriakova Classified gene: IKZF3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.493 IKZF3 Arina Puzriakova Gene: ikzf3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.492 IKZF3 Arina Puzriakova edited their review of gene: IKZF3: Changed rating: GREEN
Primary immunodeficiency or monogenic inflammatory bowel disease v2.492 IKZF3 Arina Puzriakova Added comment: Comment on mode of inheritance: Upgraded from Red to Amber but there is now enough evidence to promote this gene to Green at the next GMS panel update. Two unrelated families displaying comparable immunologic disorders including T and B cell abnormalities with recurrent infections (PMID: 34155405; 34694366). Strong functional support including animal model and in vitro studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.492 IKZF3 Arina Puzriakova Mode of inheritance for gene: IKZF3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.491 IKZF3 Arina Puzriakova Added comment: Comment on mode of pathogenicity: Variants discovered to date located in DNA binding domain of IKZF3/AIOLOS, with dominant-negative effect on WT.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.491 IKZF3 Arina Puzriakova Mode of pathogenicity for gene: IKZF3 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
Primary immunodeficiency or monogenic inflammatory bowel disease v2.490 IKZF3 Arina Puzriakova Publications for gene: IKZF3 were set to 34155405
Primary immunodeficiency or monogenic inflammatory bowel disease v2.489 IKZF3 Arina Puzriakova Tag Q4_21_rating tag was added to gene: IKZF3.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.489 IKZF3 Arina Puzriakova Phenotypes for gene: IKZF3 were changed from B cell deficiency; EBV inefctions suspectibility; hypogammaglobulinemia to Immunodeficiency 84, OMIM:619437
Primary immunodeficiency or monogenic inflammatory bowel disease v2.488 DEF6 Arina Puzriakova Tag Q4_21_rating tag was added to gene: DEF6.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.488 DEF6 Arina Puzriakova Classified gene: DEF6 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.488 DEF6 Arina Puzriakova Added comment: Comment on list classification: There are now at least 3 unrelated cases of immunodeficiency associated with different biallelic variants in this gene (PMID:31308374; 32562707). DEF6 is also associated with a relevant phenotype in OMIM (MIM# 619573) and should be promoted to Green at the next GMS panel update (tagged).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.488 DEF6 Arina Puzriakova Gene: def6 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.487 DEF6 Arina Puzriakova Publications for gene: DEF6 were set to 32086639; 31308374; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.486 DEF6 Arina Puzriakova Phenotypes for gene: DEF6 were changed from DEF6 deficiency; Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections; Diseases of Immune Dysregulation to Immunodeficiency 87 and autoimmunity, OMIM:619573; Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections
Cytopenia - NOT Fanconi anaemia v1.43 RPA1 Dmitrijs Rots gene: RPA1 was added
gene: RPA1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Literature
Mode of inheritance for gene: RPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RPA1 were set to bone marrow failure; T- and B-cell lymphopenia; pulmonary fibrosis; skin manifestations.
Penetrance for gene: RPA1 were set to unknown
Mode of pathogenicity for gene: RPA1 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: RPA1 was set to GREEN
Added comment: 4 cases with gain of function mutations with "including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations." described in
https://doi.org/10.1182/blood.2021011980
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.485 UBA1 Dmitrijs Rots reviewed gene: UBA1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34048852; Phenotypes: VEXAS autoinflammatory condition; Mode of inheritance: Other
Fetal anomalies v1.809 AR Arina Puzriakova Phenotypes for gene: AR were changed from ANDROGEN INSENSITIVITY SYNDROME; SPINAL AND BULBAR MUSCULAR ATROPHY to ANDROGEN INSENSITIVITY SYNDROME
Differences in sex development v2.52 AR Arina Puzriakova Phenotypes for gene: AR were changed from Gender Assignment Gene Panel UKGTN; Androgen insensitivity, OMIM:300068; Androgen insensitivity,partial,with/without breast cancer, OMIM:312300; Hypospadias 1,X-linked, OMIM:300633 to Androgen insensitivity, OMIM:300068; Androgen insensitivity, partial, with or without breast cancer, OMIM:312300; Hypospadias 1, X-linked, OMIM:300633
Ectodermal dysplasia v1.27 AR Arina Puzriakova Phenotypes for gene: AR were changed from Androgen insensitivity, 300068; Androgen insensitivity, partial, with or without breast cancer, 312300; Hypospadias 1, X-linked, 300633; Spinal and bulbar muscular atrophy of Kennedy, 313200 to Androgen insensitivity, OMIM:300068; Androgen insensitivity, partial, with or without breast cancer, OMIM:312300; Hypospadias 1, X-linked, OMIM:300633; Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Hereditary ataxia with onset in adulthood v2.126 RFC1 Michael Bonello reviewed gene: RFC1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32582864, 31824583, 33969391; Phenotypes: CANVAS Syndrome, Cerebellar ataxia, Idiopathic Sensory Neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Inherited ovarian cancer (without breast cancer) v2.22 AR Arina Puzriakova Phenotypes for gene: AR were changed from Androgen insensitivity, 300068; Spinal and bulbar muscular atrophy of Kennedy, 313200; Androgen insensitivity, partial, with or without breast cancer, 312300; {Prostate cancer, susceptibility to}, 176807; Hypospadias 1, X-linked, 300633 to Androgen insensitivity, OMIM:300068; Androgen insensitivity, partial, with or without breast cancer, OMIM:312300
Adult onset neurodegenerative disorder v2.250 AR Arina Puzriakova Phenotypes for gene: AR were changed from Spinal and bulbar muscular atrophy of Kennedy, 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Familial breast cancer v1.15 AR Arina Puzriakova Phenotypes for gene: AR were changed from Androgen insensitivity, 300068; Spinal and bulbar muscular atrophy of Kennedy, 313200; Androgen insensitivity, partial, with or without breast cancer, 312300; {Prostate cancer, susceptibility to}, 176807; Hypospadias 1, X-linked, 300633 to Androgen insensitivity, partial, with or without breast cancer, OMIM:312300
Intellectual disability v3.1454 AR Arina Puzriakova Phenotypes for gene: AR were changed from Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200 to Androgen insensitivity, OMIM:300068; Androgen insensitivity, partial, with or without breast cancer, OMIM:312300; Hypospadias 1, X-linked, OMIM:300633; Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Paediatric motor neuronopathies v1.72 AR Arina Puzriakova Tag Q2_21_MOI tag was added to gene: AR.
Paediatric motor neuronopathies v1.72 AR Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed to 'Other' to maintain consistency with other panels for this phenotype due to lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paediatric motor neuronopathies v1.72 AR Arina Puzriakova Mode of inheritance for gene: AR was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Adult onset neurodegenerative disorder v2.249 AR Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.249 AR Arina Puzriakova Mode of inheritance for gene: AR was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to Other
Amyotrophic lateral sclerosis/motor neuron disease v1.49 AR Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Amyotrophic lateral sclerosis/motor neuron disease v1.49 AR Arina Puzriakova Mode of inheritance for gene: AR was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to Other
Hereditary neuropathy or pain disorder v1.67 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Hereditary neuropathy v1.430 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Amyotrophic lateral sclerosis/motor neuron disease v1.48 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases, OMIM:313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Adult onset neurodegenerative disorder v2.248 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Congenital myopathy v2.68 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Distal myopathies v1.38 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Paediatric motor neuronopathies v1.71 AR_CAG Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this STR to Green at the next GMS panel update.

The AR gene was already Green on this panel for Kennedy disease, MIM# 313200 (https://panelapp.genomicsengland.co.uk/panels/79/gene/AR/); however, this was downgraded as the disease mechanism is an expansion of 36 or more CAG trinucleotide repeats in the AR gene and there is a lack of phenotypic relevance for SNVs. STR testing is appropriate route for detecting cases.; to: Comment on list classification: There is sufficient evidence to promote this STR to Green at the next GMS panel update.

The AR gene was Green on this panel for Kennedy disease, MIM# 313200 (https://panelapp.genomicsengland.co.uk/panels/79/gene/AR/); however, this has been flagged to be downgraded as the disease mechanism is an expansion of 36 or more CAG trinucleotide repeats in the AR gene and there is a lack of phenotypic relevance for SNVs. STR testing is appropriate route for detecting cases.
Adult onset neurodegenerative disorder v2.247 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Adult onset neurodegenerative disorder v2.246 FXN_GAA Arina Puzriakova Tag watchlist tag was added to STR: FXN_GAA.
Hereditary neuropathy v1.429 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Mitochondrial disorders v2.59 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Hereditary ataxia with onset in adulthood v2.126 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Adult onset hereditary spastic paraplegia v1.83 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Childhood onset hereditary spastic paraplegia v2.97 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Hereditary spastic paraplegia v1.271 FXN_GAA Arina Puzriakova Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Childhood onset dystonia, chorea or related movement disorder v1.196 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Mitochondrial disorders v2.58 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300; Friedreich ataxia with retained reflexes, 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Mitochondrial disorders v2.57 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Intellectual disability v3.1453 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia 229300; Friedreich ataxia with retained reflexes 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Possible mitochondrial disorder - nuclear genes v1.56 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Possible mitochondrial disorder - nuclear genes v1.55 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Likely inborn error of metabolism v2.196 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Undiagnosed metabolic disorders v1.494 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300; Friedreich ataxia with retained reflexes, 229300; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Undiagnosed metabolic disorders v1.493 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Adult onset neurodegenerative disorder v2.246 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreichataxia,229300Friedreichataxiawithretainedreflexes,229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Adult onset hereditary spastic paraplegia v1.82 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Childhood onset hereditary spastic paraplegia v2.96 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Optic neuropathy v2.51 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia (FRDA), 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Optic neuropathy v2.50 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Hypertrophic cardiomyopathy v2.32 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from syndromic HCM to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Ataxia and cerebellar anomalies - narrow panel v2.275 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Hereditary neuropathy or pain disorder v1.66 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Hereditary Neuropathies; Friedreich ataxia, 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Hereditary neuropathy or pain disorder v1.65 FXN Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI to 'Biallelic' as monoallelic variants have not been associated with disease. Patients either harbour a homozygous expansion or are compound heterozygous for an expansion and a point mutation.
Hereditary neuropathy or pain disorder v1.65 FXN Arina Puzriakova Mode of inheritance for gene: FXN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.64 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Hereditary neuropathy v1.428 FXN Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI to 'Biallelic' as monoallelic variants have not been associated with disease. Patients either harbour a homozygous expansion or are compound heterozygous for an expansion and a point mutation.
Hereditary neuropathy v1.428 FXN Arina Puzriakova Mode of inheritance for gene: FXN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy v1.427 FXN Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN.
Intellectual disability v3.1452 GLS_GCA Arina Puzriakova Phenotypes for STR: GLS_GCA were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412
Likely inborn error of metabolism v2.196 GLS_GCA Arina Puzriakova Phenotypes for STR: GLS_GCA were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412
Ataxia and cerebellar anomalies - narrow panel v2.275 GLS_GCA Arina Puzriakova Phenotypes for STR: GLS_GCA were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412
Intellectual disability v3.1451 GLS Arina Puzriakova commented on gene: GLS: Added 'watchlist_MOI' tag to highlight monoallelic phenotype (MIM# 618339) which is also relevant to this panel, but as there is only a single case reported to date this is not yet sufficient to update the MOI.
Intellectual disability v3.1451 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Intellectual disability v3.1450 GLS Arina Puzriakova Tag watchlist_moi tag was added to gene: GLS.
Ataxia and cerebellar anomalies - narrow panel v2.274 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412
Likely inborn error of metabolism v2.195 GLS Arina Puzriakova edited their review of gene: GLS: Changed rating: GREEN
Early onset or syndromic epilepsy v2.464 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678 to Developmental and epileptic encephalopathy 71, OMIM:618328
Likely inborn error of metabolism v2.195 GLS Arina Puzriakova commented on gene: GLS: Added 'watchlist_MOI' tag to highlight monoallelic phenotype (MIM# 618339) which is also relevant to this panel, but as there is only a single case reported to date this is not yet sufficient to update the MOI.
Undiagnosed metabolic disorders v1.493 GLS Arina Puzriakova commented on gene: GLS: Added 'watchlist_MOI' tag to highlight monoallelic phenotype (MIM# 618339) which is also relevant to this panel, but as there is only a single case reported to date this is not yet sufficient to update the MOI.
Likely inborn error of metabolism v2.195 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Likely inborn error of metabolism v2.194 GLS Arina Puzriakova Tag watchlist_moi tag was added to gene: GLS.
Undiagnosed metabolic disorders v1.493 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Undiagnosed metabolic disorders v1.492 GLS Arina Puzriakova Tag watchlist_moi tag was added to gene: GLS.
Bilateral congenital or childhood onset cataracts v2.89 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Hereditary ataxia with onset in adulthood v2.125 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Hereditary neuropathy v1.427 NOP56_GGCCTGTT Arina Puzriakova Phenotypes for STR: NOP56_GGCCTGTT were changed from to Spinocerebellar ataxia 36, OMIM:614153
Hereditary neuropathy v1.426 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36, 614153Late adult onset gait ataxia, tongue atrophy and fasciculation, distal motor neuropathy to Spinocerebellar ataxia 36, OMIM:614153
Amyotrophic lateral sclerosis/motor neuron disease v1.47 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Adult onset neurodegenerative disorder v2.245 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Adult onset neurodegenerative disorder v2.244 NOP56_GGCCTG Arina Puzriakova Tag watchlist tag was added to STR: NOP56_GGCCTG.
Hereditary ataxia v1.279 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Ataxia and cerebellar anomalies - narrow panel v2.273 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Ataxia and cerebellar anomalies - narrow panel v2.272 NOP56_GGCCTG Arina Puzriakova Tag watchlist tag was added to STR: NOP56_GGCCTG.
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.64 NOP56_GGCCTG Arina Puzriakova Phenotypes for STR: NOP56_GGCCTG were changed from Spinocerebellar ataxia 36 614153 to Spinocerebellar ataxia 36, OMIM:614153
Childhood onset dystonia, chorea or related movement disorder v1.196 NOP56 Arina Puzriakova Classified gene: NOP56 as Red List (low evidence)
Childhood onset dystonia, chorea or related movement disorder v1.196 NOP56 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red, this review is for the STR entity and not the gene entity
Childhood onset dystonia, chorea or related movement disorder v1.196 NOP56 Arina Puzriakova Gene: nop56 has been classified as Red List (Low Evidence).
Intellectual disability v3.1450 NOP56 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1450 NOP56 Arina Puzriakova Mode of inheritance for gene: NOP56 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Childhood onset dystonia, chorea or related movement disorder v1.195 NOP56 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Childhood onset dystonia, chorea or related movement disorder v1.195 NOP56 Arina Puzriakova Mode of inheritance for gene: NOP56 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Childhood onset dystonia, chorea or related movement disorder v1.194 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellar ataxia 36, 614153 to Spinocerebellar ataxia 36, OMIM:614153
Intellectual disability v3.1449 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellar ataxia 36, 614153 to Spinocerebellar ataxia 36, OMIM:614153
Childhood onset dystonia, chorea or related movement disorder v1.193 NOP56 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: NOP56.
Tag currently-ngs-unreportable tag was added to gene: NOP56.
Hereditary ataxia with onset in adulthood v2.124 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellarataxia36,614153 to Spinocerebellar ataxia 36, OMIM:614153
Intellectual disability v3.1448 NOP56 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: NOP56.
Tag currently-ngs-unreportable tag was added to gene: NOP56.
Adult onset neurodegenerative disorder v2.244 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellarataxia36,614153 to Spinocerebellar ataxia 36, OMIM:614153
Ataxia and cerebellar anomalies - narrow panel v2.272 NOP56 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: NOP56.
Tag currently-ngs-unreportable tag was added to gene: NOP56.
Hereditary ataxia v1.278 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellarataxia36,614153 to Spinocerebellar ataxia 36, OMIM:614153
Ataxia and cerebellar anomalies - narrow panel v2.272 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellarataxia36,614153 to Spinocerebellar ataxia 36, OMIM:614153
Childhood onset dystonia, chorea or related movement disorder v1.193 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellar ataxia 12, 604326 to Spinocerebellar ataxia 12, OMIM:604326
Childhood onset dystonia, chorea or related movement disorder v1.192 PPP2R2B Arina Puzriakova Classified gene: PPP2R2B as Red List (low evidence)
Childhood onset dystonia, chorea or related movement disorder v1.192 PPP2R2B Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red, this review is for the STR entity and not the gene entity
Childhood onset dystonia, chorea or related movement disorder v1.192 PPP2R2B Arina Puzriakova Gene: ppp2r2b has been classified as Red List (Low Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.191 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Childhood onset dystonia, chorea or related movement disorder v1.191 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Childhood onset dystonia, chorea or related movement disorder v1.190 PPP2R2B Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: PPP2R2B.
Tag currently-ngs-unreportable tag was added to gene: PPP2R2B.
Intellectual disability v3.1448 PPP2R2B Arina Puzriakova Mode of pathogenicity for gene: PPP2R2B 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
Adult onset dystonia, chorea or related movement disorder v1.157 PPP2R2B Arina Puzriakova Mode of pathogenicity for gene: PPP2R2B 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
Adult onset dystonia, chorea or related movement disorder v1.156 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset dystonia, chorea or related movement disorder v1.156 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from to Other
Hereditary ataxia with onset in adulthood v2.123 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia with onset in adulthood v2.123 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from Unknown to Other
Hereditary ataxia v1.277 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.277 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from to Other
Intellectual disability v3.1447 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1447 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from Other - please specify in evaluation comments to Other
Ataxia and cerebellar anomalies - narrow panel v2.271 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - narrow panel v2.271 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from Unknown to Other
Adult onset neurodegenerative disorder v2.243 PPP2R2B Arina Puzriakova Mode of pathogenicity for gene: PPP2R2B 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
Adult onset neurodegenerative disorder v2.242 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.242 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from Unknown to Other
Adult onset dystonia, chorea or related movement disorder v1.155 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from to Spinocerebellar ataxia 12, OMIM:604326
Adult onset dystonia, chorea or related movement disorder v1.154 PPP2R2B Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: PPP2R2B.
Tag currently-ngs-unreportable tag was added to gene: PPP2R2B.
Hereditary ataxia with onset in adulthood v2.122 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellarataxia12,604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary ataxia with onset in adulthood v2.121 PPP2R2B Arina Puzriakova Tag watchlist was removed from gene: PPP2R2B.
Hereditary ataxia v1.276 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellarataxia12,604326 to Spinocerebellar ataxia 12, OMIM:604326
Intellectual disability v3.1446 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellar ataxia 12, 604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary ataxia v1.275 PPP2R2B Arina Puzriakova Tag watchlist was removed from gene: PPP2R2B.
Ataxia and cerebellar anomalies - narrow panel v2.270 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellarataxia12,604326 to Spinocerebellar ataxia 12, OMIM:604326
Ataxia and cerebellar anomalies - narrow panel v2.269 PPP2R2B Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: PPP2R2B.
Tag currently-ngs-unreportable tag was added to gene: PPP2R2B.
Adult onset neurodegenerative disorder v2.241 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellarataxia12,604326 to Spinocerebellar ataxia 12, OMIM:604326
Intellectual disability v3.1445 PPP2R2B Arina Puzriakova Tag watchlist was removed from gene: PPP2R2B.
Adult onset neurodegenerative disorder v2.240 PPP2R2B Arina Puzriakova Tag watchlist was removed from gene: PPP2R2B.
Structural eye disease v1.91 FOXE3 Eleanor Williams Tag watchlist_moi tag was added to gene: FOXE3.
Structural eye disease v1.91 FOXE3 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving mode of inheritance as biallelic for now. 2 monoallelic cases with coloboma, or both coloboma and microphthalmia so flagged with MOI_watchlist tag.
Structural eye disease v1.91 FOXE3 Eleanor Williams Mode of inheritance for gene: FOXE3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.90 FOXE3 Eleanor Williams Phenotypes for gene: FOXE3 were changed from Anterior segment mesenchymal dysgenesis 107250; Anterior segment dysgenesis 2, multiple subtypes 610256 to Anterior segment mesenchymal dysgenesis, OMIM:107250; Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256
Structural eye disease v1.89 FOXE3 Eleanor Williams Publications for gene: FOXE3 were set to 16826526; 24859618, 19708017; 20361012; 11159941; 27218149; 21150893
Structural eye disease v1.88 FOXE3 Eleanor Williams changed review comment from: Review of mode of inheritance:

There are many reported cases of biallelic variants in FOXE3 associated with an eye phenotype, particularly cataracts, aphakia, microphthalmia and sclerocornea (PMID: 27218149 Khan et al 2016, PMID: 16826526 Valleix et al 2006, PMID: 19708017 Iseri et al 2009, PMID: 20140963 Reis et al 2010, PMID: 20664696 Ali et al 2010, PMID: 20361012 Anjum et al 2010, PMID: 24019743 Pantoja-Melendez et al 2013, PMID: 27669367 Saboo et al 2017, PMID: 29878917 Quiroz-Casian et al 2018, PMID: 32436650 Taha Najim et al 2020, PMID: 34046667 Reis et al 2021). Glaucoma is also noted in some individuals. Heterozygous carriers are largely unaffected in these cases.

Patients with monoallelic variants in FOXE3 and an eye phenotype are also reported:

PMID: 11159941 - Semina et al 2001 - screened FOXE3 in a cohort of 161 unrelated individuals affected with anterior segment ocular disorders and identified a 1 bp insertion in FOXE3 in a proband and affected mother that was not found in controls. Both affected individuals had prominent anterior Schwalbe’s line (posterior embryotoxon) and cataracts.

PMID: 19708017 - Iseri et al 2009 - identified 2 pedigrees with dominant mutations in the FOXE3 gene by screening a large cohort of 236 anophthalmia-microphthalmia subjects; one with anterior segment anomalies, including Peters’ anomaly, early onset cataract, and coloboma, and another with microphthalmia,coloboma, and cerulean type (blue dot) cataracts.

PMID: 20806047 - Bremond-Ginac et al 2010 - a dominant mutation at the stop codon of FOXE3, c.959G>C (p.X320SerextX72), was identified in a patient with congenital cataract.

PMID: 21150893 - Doucette et al 2011 - sequenced 9 candidate genes in a large Newfoundland family with 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly and found a c.959G>T) substitution that replaces the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Analysis of lympohocytes suggests the c.959T allele is absent rather than an extended protein being expressed.

PMID: 11980846 - Ormestad et al 2002 - one individual with Peters anomaly (with eccentric corneal opacities and glaucoma but not cataract) was found to be heterozygous for a nonconservative missense mutation in FOXE3. 40% of mice heterozygous for Foxe3(dyl) have corneal and lenticular defects.

PMID: 34046667 - Reis et al 2021 - 2 families reported with dominant pathogenic extension alleles which modify the stop codon but keep the amino acids in frame, adding a 72–amino acid nonsense peptide. Cataracts were found in all cases where the lens could be evaluated. Eye size was normal in all individuals, but mild anterior segment anomalies affecting the cornea and/or iris were noted in some individuals. Sclerocornea was observed in two family members (15C and 16B).; to: Review of mode of inheritance:

There are many reported cases of biallelic variants in FOXE3 associated with an eye phenotype, particularly cataracts, aphakia, microphthalmia and sclerocornea (PMID: 27218149 Khan et al 2016, PMID: 16826526 Valleix et al 2006, PMID: 19708017 Iseri et al 2009, PMID: 20140963 Reis et al 2010, PMID: 20664696 Ali et al 2010, PMID: 20361012 Anjum et al 2010, PMID: 24019743 Pantoja-Melendez et al 2013, PMID: 27669367 Saboo et al 2017, PMID: 29878917 Quiroz-Casian et al 2018, PMID: 32436650 Taha Najim et al 2020, PMID: 34046667 Reis et al 2021). Glaucoma is also noted in some individuals. Heterozygous carriers are largely unaffected in these cases.

Patients with monoallelic variants in FOXE3 and an eye phenotype are also reported, but only 2 patients show coloboma, or both coloboma and microphthalmia (both reported in Iseri et al 2009).

PMID: 11159941 - Semina et al 2001 - screened FOXE3 in a cohort of 161 unrelated individuals affected with anterior segment ocular disorders and identified a 1 bp insertion in FOXE3 in a proband and affected mother that was not found in controls. Both affected individuals had prominent anterior Schwalbe’s line (posterior embryotoxon) and cataracts.

PMID: 19708017 - Iseri et al 2009 - identified 2 pedigrees with dominant mutations in the FOXE3 gene by screening a large cohort of 236 anophthalmia-microphthalmia subjects; one with anterior segment anomalies, including Peters’ anomaly, early onset cataract, and coloboma, and another with microphthalmia, coloboma, and cerulean type (blue dot) cataracts.

PMID: 20806047 - Bremond-Ginac et al 2010 - a dominant mutation at the stop codon of FOXE3, c.959G>C (p.X320SerextX72), was identified in a patient with congenital cataract.

PMID: 21150893 - Doucette et al 2011 - sequenced 9 candidate genes in a large Newfoundland family with 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly and found a c.959G>T) substitution that replaces the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Analysis of lympohocytes suggests the c.959T allele is absent rather than an extended protein being expressed.

PMID: 11980846 - Ormestad et al 2002 - one individual with Peters anomaly (with eccentric corneal opacities and glaucoma but not cataract) was found to be heterozygous for a nonconservative missense mutation in FOXE3. 40% of mice heterozygous for Foxe3(dyl) have corneal and lenticular defects.

PMID: 34046667 - Reis et al 2021 - 2 families reported with dominant pathogenic extension alleles which modify the stop codon but keep the amino acids in frame, adding a 72–amino acid nonsense peptide. Cataracts were found in all cases where the lens could be evaluated. Eye size was normal in all individuals, but mild anterior segment anomalies affecting the cornea and/or iris were noted in some individuals. Sclerocornea was observed in two family members (15C and 16B).
Adult onset dystonia, chorea or related movement disorder v1.154 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Adult onset dystonia, chorea or related movement disorder v1.153 PPP2R2B_CAG Arina Puzriakova Tag watchlist tag was added to STR: PPP2R2B_CAG.
Intellectual disability v3.1445 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary ataxia with onset in adulthood v2.121 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary neuropathy v1.425 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326; Adult onset cerebellar ataxia, tremor of head and arms, subclinical sensory-motor axonal neuropathy; neuropathy minor feature to Spinocerebellar ataxia 12, OMIM:604326
Adult onset neurodegenerative disorder v2.240 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Adult onset neurodegenerative disorder v2.239 PPP2R2B_CAG Arina Puzriakova Tag watchlist tag was added to STR: PPP2R2B_CAG.
Adult onset hereditary spastic paraplegia v1.82 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Childhood onset hereditary spastic paraplegia v2.96 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary spastic paraplegia v1.270 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Hereditary ataxia v1.275 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Ataxia and cerebellar anomalies - narrow panel v2.269 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Ataxia and cerebellar anomalies - narrow panel v2.268 PPP2R2B_CAG Arina Puzriakova Tag watchlist tag was added to STR: PPP2R2B_CAG.
Parkinson Disease and Complex Parkinsonism v1.92 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Childhood onset dystonia, chorea or related movement disorder v1.190 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17, 607136 to Spinocerebellar ataxia 17, OMIM:607136
Hereditary ataxia with onset in adulthood v2.120 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Adult onset hereditary spastic paraplegia v1.81 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Childhood onset hereditary spastic paraplegia v2.95 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Hereditary spastic paraplegia v1.269 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Hereditary ataxia v1.274 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Ataxia and cerebellar anomalies - narrow panel v2.268 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Ataxia and cerebellar anomalies - narrow panel v2.267 TBP_CAG Arina Puzriakova Tag watchlist tag was added to STR: TBP_CAG.
Brain channelopathy v1.70 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136
Adult onset dystonia, chorea or related movement disorder v1.153 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Adult onset neurodegenerative disorder v2.239 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Adult onset neurodegenerative disorder v2.238 TBP_CAG Arina Puzriakova Tag watchlist tag was added to STR: TBP_CAG.
Paroxysmal central nervous system disorders v1.34 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.63 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Parkinson Disease and Complex Parkinsonism v1.91 TBP_CAG Arina Puzriakova Phenotypes for STR: TBP_CAG were changed from Spinocerebellar ataxia 17 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Intellectual disability v3.1444 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1444 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from Other - please specify in evaluation comments to Other
Intellectual disability v3.1443 TBP Arina Puzriakova Mode of pathogenicity for gene: TBP 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
Adult onset neurodegenerative disorder v2.238 TBP Arina Puzriakova Mode of pathogenicity for gene: TBP 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
Paroxysmal central nervous system disorders v1.33 TBP Arina Puzriakova Mode of pathogenicity for gene: TBP 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
Adult onset dystonia, chorea or related movement disorder v1.152 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset dystonia, chorea or related movement disorder v1.152 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Hereditary ataxia with onset in adulthood v2.119 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia with onset in adulthood v2.119 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from Unknown to Other
Adult onset neurodegenerative disorder v2.237 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.237 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Paroxysmal central nervous system disorders v1.32 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paroxysmal central nervous system disorders v1.32 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from to Other
Hereditary ataxia v1.273 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.273 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from to Other
Ataxia and cerebellar anomalies - narrow panel v2.267 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - narrow panel v2.267 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from Unknown to Other
Parkinson Disease and Complex Parkinsonism v1.90 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.90 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Adult onset dystonia, chorea or related movement disorder v1.151 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from {Parkinson disease, susceptibility to}, 168600; Mohr-Tranebjaerg syndrome, 304700; Spinocerebellar ataxia 17, 607136 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Adult onset dystonia, chorea or related movement disorder v1.150 TBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: TBP.
Tag currently-ngs-unreportable tag was added to gene: TBP.
Intellectual disability v3.1442 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellar ataxia 17, 607136; {Parkinson disease, susceptibility to}, 168600 to Spinocerebellar ataxia 17, OMIM:607136
Hereditary ataxia with onset in adulthood v2.118 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellarataxia17,607136{Parkinsondisease,susceptibilityto},168600 to Spinocerebellar ataxia 17, OMIM:607136
Intellectual disability v3.1441 TBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: TBP.
Tag currently-ngs-unreportable tag was added to gene: TBP.
Adult onset neurodegenerative disorder v2.236 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellar ataxia 17, 607136; Spinocerebellarataxia17,607136{Parkinsondisease,susceptibilityto},168600; {Parkinson disease, susceptibility to}, 168600 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Paroxysmal central nervous system disorders v1.31 TBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: TBP.
Tag currently-ngs-unreportable tag was added to gene: TBP.
Paroxysmal central nervous system disorders v1.31 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Hereditary ataxia v1.272 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellarataxia17,607136{Parkinsondisease,susceptibilityto},168600 to Spinocerebellar ataxia 17, OMIM:607136
Ataxia and cerebellar anomalies - narrow panel v2.266 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellarataxia17,607136{Parkinsondisease,susceptibilityto},168600 to Spinocerebellar ataxia 17, OMIM:607136
Ataxia and cerebellar anomalies - narrow panel v2.265 TBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: TBP.
Tag currently-ngs-unreportable tag was added to gene: TBP.
Parkinson Disease and Complex Parkinsonism v1.89 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellar ataxia 17, 607136; {Parkinson disease, susceptibility to}, 168600 to Spinocerebellar ataxia 17, OMIM:607136; {Parkinson disease, susceptibility to}, OMIM:168600
Parkinson Disease and Complex Parkinsonism v1.88 TBP Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: TBP.
Adult onset leukodystrophy v1.35 RNASET2 Ivone Leong Tag Q4_21_expert_review tag was added to gene: RNASET2.
Adult onset leukodystrophy v1.35 POLR1C Ivone Leong Tag Q4_21_expert_review tag was added to gene: POLR1C.
Adult onset leukodystrophy v1.35 MARS Ivone Leong Tag Q4_21_expert_review tag was added to gene: MARS.
Tag Q4_21_phenotype tag was added to gene: MARS.
Rare genetic inflammatory skin disorders v1.42 RNU12 Eleanor Williams Tag Q4_21_phenotype tag was added to gene: RNU12.
Rare genetic inflammatory skin disorders v1.42 RNU12 Eleanor Williams Classified gene: RNU12 as Amber List (moderate evidence)
Rare genetic inflammatory skin disorders v1.42 RNU12 Eleanor Williams Added comment: Comment on list classification: Promoted from red to amber. It could be promoted to green after GMS review if the working group decide that the phenotype is appropriate for this panel. However, variants in this gene would not currently be reported as it is not a protein coding gene. An Ensembl ID also needs to be added before it is promoted to green.
Rare genetic inflammatory skin disorders v1.42 RNU12 Eleanor Williams Gene: rnu12 has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v1.41 RNU12 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: RNU12.
Tag Q4_21_expert_review tag was added to gene: RNU12.
Tag Q4_21_rating tag was added to gene: RNU12.
Rare genetic inflammatory skin disorders v1.41 RNU12 Eleanor Williams changed review comment from: Note RNU12 has Ensembl gene ID ENSG00000276027 in GRCh38. It is not listed in OMIM. I

PMID: 34085356 (Xing et al 2021) report the analysis of 5 patients from 4 unrelated families with clinical features of CDAGS (Craniosynostosis and clavicular hypoplasia; Delayed closure of the fontanelles and cranial defects (and deafness in some patients); Anal anomalies; Genitourinary malformations; and Skin eruption, including porokeratosis). WES and Sanger sequencing was used to identify rare biallelic variants in RNU12. All affected individuals were compound heterozygous, with all 5 patients sharing NC_000022.10:g.43011402C>T, which alters a highly conserved nucleotide. Each individual also carried another variant (4 different variants) in RNU12 thought to disrupt the secondary structure or the Sm binding site of the RNU12 snRNA. All 5 individuals were reported to have skin anomalies; erythematous cutaneous eruption consistent with porokeratosis (1), erythematous skin eruption involving the cheeks, arms, and legs (1), porokeratosis (2 siblings), disseminated dermatosis (1 individual)
Sources: Literature; to: Note RNU12 has Ensembl gene ID ENSG00000276027 in GRCh38. It is not listed in OMIM. It encodes a small nuclear RNA.

PMID: 34085356 (Xing et al 2021) report the analysis of 5 patients from 4 unrelated families with clinical features of CDAGS (Craniosynostosis and clavicular hypoplasia; Delayed closure of the fontanelles and cranial defects (and deafness in some patients); Anal anomalies; Genitourinary malformations; and Skin eruption, including porokeratosis). WES and Sanger sequencing was used to identify rare biallelic variants in RNU12. All affected individuals were compound heterozygous, with all 5 patients sharing NC_000022.10:g.43011402C>T, which alters a highly conserved nucleotide. Each individual also carried another variant (4 different variants) in RNU12 thought to disrupt the secondary structure or the Sm binding site of the RNU12 snRNA. All 5 individuals were reported to have skin anomalies; erythematous cutaneous eruption consistent with porokeratosis (1), erythematous skin eruption involving the cheeks, arms, and legs (1), porokeratosis (2 siblings), disseminated dermatosis (1 individual)
Sources: Literature
Rare genetic inflammatory skin disorders v1.41 RNU12 Eleanor Williams gene: RNU12 was added
gene: RNU12 was added to Rare genetic inflammatory skin disorders. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 34085356
Phenotypes for gene: RNU12 were set to porokeratosis; erythematous cutaneous eruption
Review for gene: RNU12 was set to GREEN
Added comment: Note RNU12 has Ensembl gene ID ENSG00000276027 in GRCh38. It is not listed in OMIM. I

PMID: 34085356 (Xing et al 2021) report the analysis of 5 patients from 4 unrelated families with clinical features of CDAGS (Craniosynostosis and clavicular hypoplasia; Delayed closure of the fontanelles and cranial defects (and deafness in some patients); Anal anomalies; Genitourinary malformations; and Skin eruption, including porokeratosis). WES and Sanger sequencing was used to identify rare biallelic variants in RNU12. All affected individuals were compound heterozygous, with all 5 patients sharing NC_000022.10:g.43011402C>T, which alters a highly conserved nucleotide. Each individual also carried another variant (4 different variants) in RNU12 thought to disrupt the secondary structure or the Sm binding site of the RNU12 snRNA. All 5 individuals were reported to have skin anomalies; erythematous cutaneous eruption consistent with porokeratosis (1), erythematous skin eruption involving the cheeks, arms, and legs (1), porokeratosis (2 siblings), disseminated dermatosis (1 individual)
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v1.189 HTT Arina Puzriakova Publications for gene: HTT were set to
Intellectual disability v3.1441 HTT Arina Puzriakova Publications for gene: HTT were set to 26740508; 27329733
Childhood onset dystonia, chorea or related movement disorder v1.188 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Biallelic SNVs have been reported for Lopes-Maciel-Rodan syndrome
Childhood onset dystonia, chorea or related movement disorder v1.188 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.187 HTT Arina Puzriakova Classified gene: HTT as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.187 HTT Arina Puzriakova Gene: htt has been classified as Amber List (Moderate Evidence).
Adult onset leukodystrophy v1.35 EARS2 Ivone Leong Tag Q4_21_expert_review tag was added to gene: EARS2.
Childhood onset dystonia, chorea or related movement disorder v1.186 HTT Arina Puzriakova reviewed gene: HTT: Rating: ; Mode of pathogenicity: None; Publications: 26740508, 27329733, 33432339; Phenotypes: Lopes-Maciel-Rodan syndrome, OMIM:617435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.186 HTT Arina Puzriakova Tag watchlist tag was added to gene: HTT.
Adult onset leukodystrophy v1.35 CTC1 Ivone Leong Phenotypes for gene: CTC1 were changed from Cerebroretinal microangiopathy with calcifications and cysts, 612199 to Cerebroretinal microangiopathy with calcifications and cysts, OMIM:612199
Adult onset leukodystrophy v1.34 CTC1 Ivone Leong Publications for gene: CTC1 were set to 27159321; 25527826; 28334938; 20301621; 24357685
Adult onset dystonia, chorea or related movement disorder v1.150 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset dystonia, chorea or related movement disorder v1.150 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Hereditary ataxia with onset in adulthood v2.117 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism. Biallelic variants not relevant to this panel.
Hereditary ataxia with onset in adulthood v2.117 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to Other
Mitochondrial disorders v2.57 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Mitochondrial disorders v2.57 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Possible mitochondrial disorder - nuclear genes v1.55 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Possible mitochondrial disorder - nuclear genes v1.55 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Adult onset neurodegenerative disorder v2.235 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.235 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Paroxysmal central nervous system disorders v1.30 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paroxysmal central nervous system disorders v1.30 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Structural basal ganglia disorders v1.25 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Structural basal ganglia disorders v1.25 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Brain channelopathy v1.69 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Brain channelopathy v1.69 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Parkinson Disease and Complex Parkinsonism v1.88 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.88 HTT Arina Puzriakova Mode of inheritance for gene: HTT was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Adult onset leukodystrophy v1.33 COL4A2 Ivone Leong Tag Q4_21_expert_review tag was added to gene: COL4A2.
Tag Q4_21_phenotype tag was added to gene: COL4A2.
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is not enough evidence to support a gene-disease association as only 2 of 3 cases had seizures.
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong Tag Q4_21_rating was removed from gene: COLGALT1.
Tag watchlist tag was added to gene: COLGALT1.
Inherited white matter disorders v1.147 COLGALT1 Ivone Leong Tag Q4_21_rating was removed from gene: COLGALT1.
Inherited white matter disorders v1.147 COLGALT1 Ivone Leong Classified gene: COLGALT1 as Green List (high evidence)
Inherited white matter disorders v1.147 COLGALT1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as per my review.
Inherited white matter disorders v1.147 COLGALT1 Ivone Leong Gene: colgalt1 has been classified as Green List (High Evidence).
Inherited white matter disorders v1.146 COLGALT1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association.
Familial cerebral small vessel disease v1.13 COLGALT1 Ivone Leong Classified gene: COLGALT1 as Green List (high evidence)
Familial cerebral small vessel disease v1.13 COLGALT1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as per my review.
Familial cerebral small vessel disease v1.13 COLGALT1 Ivone Leong Gene: colgalt1 has been classified as Green List (High Evidence).
Familial cerebral small vessel disease v1.12 COLGALT1 Ivone Leong Tag Q4_21_rating was removed from gene: COLGALT1.
Familial cerebral small vessel disease v1.12 COLGALT1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association.
Familial cerebral small vessel disease v1.12 COLGALT1 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.216
Familial cerebral small vessel disease v1.12 COLGALT1 Ivone Leong gene: COLGALT1 was added
gene: COLGALT1 was added to Familial cerebral small vessel disease. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: COLGALT1.
Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COLGALT1 were set to 30412317; 33709034; 31759980
Phenotypes for gene: COLGALT1 were set to Brain small vessel disease 3, OMIM:618360
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.216
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong gene: COLGALT1 was added
gene: COLGALT1 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: COLGALT1.
Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COLGALT1 were set to 30412317; 33709034; 31759980
Phenotypes for gene: COLGALT1 were set to Brain small vessel disease 3, OMIM:618360
Inherited white matter disorders v1.146 COLGALT1 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.216
Inherited white matter disorders v1.146 COLGALT1 Ivone Leong gene: COLGALT1 was added
gene: COLGALT1 was added to Inherited white matter disorders. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: COLGALT1.
Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COLGALT1 were set to 30412317; 33709034; 31759980
Phenotypes for gene: COLGALT1 were set to Brain small vessel disease 3, OMIM:618360
White matter disorders and cerebral calcification - narrow panel v1.216 COLGALT1 Ivone Leong Phenotypes for gene: COLGALT1 were changed from Brain small vessel disease 3 MIM#618360 to Brain small vessel disease 3, OMIM:618360
White matter disorders and cerebral calcification - narrow panel v1.215 COLGALT1 Ivone Leong Classified gene: COLGALT1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.215 COLGALT1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.215 COLGALT1 Ivone Leong Gene: colgalt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1440 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Lopes-Maciel-Rodan syndrome, 617435; LOMARS; Intellectual disability to Lopes-Maciel-Rodan syndrome, OMIM:617435; LOMARS
Childhood onset dystonia, chorea or related movement disorder v1.186 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease, 143100 to Lopes-Maciel-Rodan syndrome, OMIM:617435; LOMARS
Adult onset dystonia, chorea or related movement disorder v1.149 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease to Huntington disease, OMIM:143100
Adult onset dystonia, chorea or related movement disorder v1.148 HTT Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: HTT.
Tag currently-ngs-unreportable tag was added to gene: HTT.
Hereditary ataxia with onset in adulthood v2.116 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease 143100; Lopes-Maciel-Rodan syndrome, 617432 to Huntington disease, OMIM:143100
Mitochondrial disorders v2.56 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease, 143100 to Huntington disease, OMIM:143100
Mitochondrial disorders v2.55 HTT Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: HTT.
Tag currently-ngs-unreportable tag was added to gene: HTT.
Possible mitochondrial disorder - nuclear genes v1.54 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease, 143100 to Huntington disease, OMIM:143100
Possible mitochondrial disorder - nuclear genes v1.53 HTT Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: HTT.
Tag currently-ngs-unreportable tag was added to gene: HTT.
Adult onset neurodegenerative disorder v2.234 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease 143100; Huntingtons disease (HD) to Huntington disease, OMIM:143100
Paroxysmal central nervous system disorders v1.29 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease, 143100 to Huntington disease, OMIM:143100
Paroxysmal central nervous system disorders v1.28 HTT Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: HTT.
Tag currently-ngs-unreportable tag was added to gene: HTT.
Structural basal ganglia disorders v1.24 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Brain channelopathy v1.68 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Parkinson Disease and Complex Parkinsonism v1.87 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Huntingtons disease (HD) to Huntington disease, OMIM:143100
Adult onset dystonia, chorea or related movement disorder v1.148 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Hereditary ataxia with onset in adulthood v2.115 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Adult onset neurodegenerative disorder v2.233 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Adult onset hereditary spastic paraplegia v1.80 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Childhood onset hereditary spastic paraplegia v2.94 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Hereditary spastic paraplegia v1.268 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Structural basal ganglia disorders v1.23 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Hereditary ataxia v1.271 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Ataxia and cerebellar anomalies - narrow panel v2.265 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Brain channelopathy v1.67 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
White matter disorders and cerebral calcification - narrow panel v1.214 COLGALT1 Ivone Leong Tag Q4_21_rating tag was added to gene: COLGALT1.
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.62 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Parkinson Disease and Complex Parkinsonism v1.86 HTT_CAG Arina Puzriakova Phenotypes for STR: HTT_CAG were changed from Huntington disease 143100 to Huntington disease, OMIM:143100
Hereditary neuropathy v1.424 FMR1_CGG Arina Puzriakova Phenotypes for STR: FMR1_CGG were changed from Fragile X syndrome 300624; Late onset tremor, ataxia, parkinsonism, sensory axonal neuropathy, middle cerebellar peduncle changes on MRI to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Hereditary neuropathy v1.423 FMR1_CGG Arina Puzriakova Tag currently-ngs-unreportable was removed from STR: FMR1_CGG.
Intellectual disability v3.1439 FMR1_CGG Arina Puzriakova Phenotypes for STR: FMR1_CGG were changed from Fragile X syndrome 300624 to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Intellectual disability v3.1438 FMR1_CGG Arina Puzriakova Tag currently-ngs-unreportable was removed from STR: FMR1_CGG.
Hereditary ataxia with onset in adulthood v2.114 FMR1_CGG Arina Puzriakova Phenotypes for STR: FMR1_CGG were changed from Fragile X syndrome, 300624 to Fragile X tremor/ataxia syndrome, OMIM:300623
Hereditary ataxia v1.270 FMR1_CGG Arina Puzriakova Phenotypes for STR: FMR1_CGG were changed from Fragile X syndrome 300624 to Fragile X tremor/ataxia syndrome, OMIM:300623
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.58 SMAD3 Eleanor Williams Classified gene: SMAD3 as Amber List (moderate evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.58 SMAD3 Eleanor Williams Added comment: Comment on list classification: On advice from Genomics England clinical team, promoting this gene from grey to amber. The number of cases with a craniosynostosis phenotype is borderline so rating as amber for now. Only 1 biallelic case reported so far so keeping the mode of inheritance as monoallelic.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.58 SMAD3 Eleanor Williams Gene: smad3 has been classified as Amber List (Moderate Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.57 SMAD3 Eleanor Williams Phenotypes for gene: SMAD3 were changed from Loeys-Dietz syndrome 3, MIM# 613795 to Loeys-Dietz syndrome 3, OMIM:613795
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.56 SMAD3 Eleanor Williams Publications for gene: SMAD3 were set to 20301312; 29392890
Primary ovarian insufficiency v1.55 FMR1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Primary ovarian insufficiency v1.55 FMR1 Arina Puzriakova Mode of inheritance for gene: FMR1 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to Other
Ataxia and cerebellar anomalies - narrow panel v2.264 FMR1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FMR1.
Intellectual disability v3.1438 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from Fragile X syndrome, 300624Fragile X tremor/ataxia syndrome, 300623Premature ovarian failure 1, 311360; PREMATURE OVARIAN FAILURE SYNDROME TYPE 1 (POF1) to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Intellectual disability v3.1437 FMR1 Arina Puzriakova Tag currently-ngs-unreportable was removed from gene: FMR1.
Hereditary ataxia v1.269 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related premature ovarian insufficiency (POI); FragileXtremor/ataxiasyndrome,300623; males with a tremor phenotype to Fragile X tremor/ataxia syndrome, OMIM:300623
Ataxia and cerebellar anomalies - narrow panel v2.264 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related premature ovarian insufficiency (POI); males with a tremor phenotype; FragileXtremor/ataxiasyndrome,300623 to Fragile X tremor/ataxia syndrome, OMIM:300623
Hereditary ataxia with onset in adulthood v2.113 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from FragileXtremor/ataxiasyndrome,300623; Fragile X tremor/ataxia syndrome; FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related premature ovarian insufficiency (POI); males with a tremor phenotype to Fragile X tremor/ataxia syndrome, OMIM:300623
Fetal anomalies v1.808 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from FRAGILE X SYNDROME; FRAGILE X TREMOR/ATAXIA SYNDROME; PREMATURE OVARIAN FAILURE SYNDROME TYPE 1 to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Adult onset neurodegenerative disorder v2.232 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related premature ovarian insufficiency (POI); males with a tremor phenotype; FragileXtremor/ataxiasyndrome,300623 to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Hydrocephalus v2.124 FMR1 Arina Puzriakova Tag currently-ngs-unreportable was removed from gene: FMR1.
Hydrocephalus v2.124 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from Fragile X syndrome 300624 to Fragile X syndrome, OMIM:300624
Hydrocephalus v2.123 FMR1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FMR1.
Tag currently-ngs-unreportable tag was added to gene: FMR1.
Primary ovarian insufficiency v1.54 FMR1_CGG Arina Puzriakova Phenotypes for STR: FMR1_CGG were changed from Fragile X syndrome 300624 to Premature ovarian failure 1, OMIM:311360
Primary ovarian insufficiency v1.53 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from Fragile X syndrome, 300624; Fragile X tremor ataxia syndrome, 300623; Premature ovarian failure 1, 311360; Premature Ovarian Insufficiency to Premature ovarian failure 1, OMIM:311360
Non-syndromic familial congenital anorectal malformations v1.8 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: Updating the mode of inheritance to X-linked: hemizygous mutation in males, monallelic mutations in females after advice from the Genomics England clinical team. There are 5 reported relevant cases in females.
Non-syndromic familial congenital anorectal malformations v1.8 MED12 Eleanor Williams Mode of inheritance for gene: MED12 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)
Skeletal dysplasia v2.154 ZNF687 Eleanor Williams Phenotypes for gene: ZNF687 were changed from Paget Disease of Bone with associated Giant Cell Tumour. to Paget disease of bone 6, OMIM:616833
Skeletal dysplasia v2.153 ZNF687 Eleanor Williams Publications for gene: ZNF687 were set to PMID: 29493781, PMID: 28968976, PMID: 26849110
Skeletal dysplasia v2.152 ZNF687 Eleanor Williams Classified gene: ZNF687 as Amber List (moderate evidence)
Skeletal dysplasia v2.152 ZNF687 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for a green rating following GMS review.
Skeletal dysplasia v2.152 ZNF687 Eleanor Williams Gene: znf687 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.151 ZNF687 Eleanor Williams Tag Q4_21_rating tag was added to gene: ZNF687.
Skeletal dysplasia v2.151 ZNF687 Eleanor Williams reviewed gene: ZNF687: Rating: GREEN; Mode of pathogenicity: None; Publications: 29493781, 26849110; Phenotypes: Paget disease of bone 6, OMIM:616833; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary spastic paraplegia v1.267 KIDINS220 Sarah Leigh Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity OMIM:617296
Hereditary spastic paraplegia v1.266 KIDINS220 Sarah Leigh Publications for gene: KIDINS220 were set to 27005418; 29667355; 31630374
COVID-19 research v1.85 LZTFL1 Sarah Leigh Classified gene: LZTFL1 as Red List (low evidence)
COVID-19 research v1.85 LZTFL1 Sarah Leigh Gene: lztfl1 has been classified as Red List (Low Evidence).
COVID-19 research v1.84 LZTFL1 Sarah Leigh reviewed gene: LZTFL1: Rating: RED; 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
COVID-19 research v1.84 LZTFL1 Sarah Leigh Phenotypes for gene: LZTFL1 were changed from Visceral Heterotaxy; Bardet-Biedl Syndrome 17 to Bardet-Biedl syndrome 17 OMIM:615994
COVID-19 research v1.83 LZTFL1 Sarah Leigh Publications for gene: LZTFL1 were set to 22510444; 23692385
COVID-19 research v1.82 LZTFL1 Sarah Leigh Entity copied from Primary ciliary disorders v1.36
COVID-19 research v1.82 LZTFL1 Sarah Leigh gene: LZTFL1 was added
gene: LZTFL1 was added to COVID-19 research. Sources: UKGTN,Expert Review Amber
watchlist tags were added to gene: LZTFL1.
Mode of inheritance for gene: LZTFL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LZTFL1 were set to 22510444; 23692385
Phenotypes for gene: LZTFL1 were set to Visceral Heterotaxy; Bardet-Biedl Syndrome 17
Penetrance for gene: LZTFL1 were set to Complete
Primary ciliary disorders v1.36 LZTFL1 Sarah Leigh Phenotypes for gene: LZTFL1 were changed from Visceral Heterotaxy; Bardet-Biedl Syndrome 17 to Visceral Heterotaxy; Bardet-Biedl Syndrome 17
Publications for gene: LZTFL1 were updated from 22510444; 23692385 to 22510444; 23692385
Intellectual disability v3.1437 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Intellectual disability v3.1436 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1436 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from BIALLELIC, autosomal or pseudoautosomal to Other
Adult onset neurodegenerative disorder v2.231 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.231 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from Unknown to Other
Hereditary ataxia v1.268 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.268 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from to Other
Ataxia and cerebellar anomalies - narrow panel v2.263 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - narrow panel v2.263 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from Unknown to Other
Hereditary ataxia with onset in adulthood v2.112 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia with onset in adulthood v2.112 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from Unknown to Other
Adult onset dystonia, chorea or related movement disorder v1.147 ATXN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN1.
Tag currently-ngs-unreportable tag was added to gene: ATXN1.
Adult onset dystonia, chorea or related movement disorder v1.147 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset dystonia, chorea or related movement disorder v1.147 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from to Other
Childhood onset dystonia, chorea or related movement disorder v1.185 ATXN1 Arina Puzriakova Mode of pathogenicity for gene: ATXN1 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
Childhood onset dystonia, chorea or related movement disorder v1.184 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellar ataxia 1, 164400 to Spinocerebellar ataxia 1, OMIM:164400
Adult onset dystonia, chorea or related movement disorder v1.146 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from to Spinocerebellar ataxia 1, OMIM:164400
Hereditary ataxia with onset in adulthood v2.111 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellar ataxia 1, 164400; Spinocerebellarataxia1,164400 to Spinocerebellar ataxia 1, OMIM:164400
Adult onset neurodegenerative disorder v2.230 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellarataxia1,164400 to Spinocerebellar ataxia 1, OMIM:164400
Hereditary ataxia v1.267 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellarataxia1,164400 to Spinocerebellar ataxia 1, OMIM:164400
Ataxia and cerebellar anomalies - narrow panel v2.262 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellarataxia1,164400 to Spinocerebellar ataxia 1, OMIM:164400
Ataxia and cerebellar anomalies - narrow panel v2.261 ATXN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN1.
Tag currently-ngs-unreportable tag was added to gene: ATXN1.
Adult onset dystonia, chorea or related movement disorder v1.145 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Adult onset dystonia, chorea or related movement disorder v1.144 ATXN1_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN1_CAG.
Intellectual disability v3.1435 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Hereditary ataxia with onset in adulthood v2.110 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Hereditary neuropathy v1.423 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Adult onset neurodegenerative disorder v2.229 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Adult onset neurodegenerative disorder v2.228 ATXN1_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN1_CAG.
Adult onset hereditary spastic paraplegia v1.79 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Childhood onset hereditary spastic paraplegia v2.93 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Hereditary spastic paraplegia v1.265 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Hereditary ataxia v1.266 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Ataxia and cerebellar anomalies - narrow panel v2.261 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Ataxia and cerebellar anomalies - narrow panel v2.260 ATXN1_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN1_CAG.
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.61 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Parkinson Disease and Complex Parkinsonism v1.85 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Intellectual disability v3.1434 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Intellectual disability; dystonia to Neurodevelopmental disorder, MONDO:0700092; Paroxysmal dystonia, MONDO:0016058
Adult onset dystonia, chorea or related movement disorder v1.144 JPH3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset dystonia, chorea or related movement disorder v1.144 JPH3 Arina Puzriakova Mode of inheritance for gene: JPH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Adult onset neurodegenerative disorder v2.228 JPH3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.228 JPH3 Arina Puzriakova Mode of inheritance for gene: JPH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.60 JPH3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.60 JPH3 Arina Puzriakova Mode of inheritance for gene: JPH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Parkinson Disease and Complex Parkinsonism v1.84 JPH3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.84 JPH3 Arina Puzriakova Mode of inheritance for gene: JPH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.59 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Adult onset neurodegenerative disorder v2.227 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Adult onset dystonia, chorea or related movement disorder v1.143 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Huntington disease-like 2 to Huntington disease-like 2, OMIM:606438
Parkinson Disease and Complex Parkinsonism v1.83 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Adult onset dystonia, chorea or related movement disorder v1.142 JPH3_CTG Arina Puzriakova Phenotypes for STR: JPH3_CTG were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Adult onset neurodegenerative disorder v2.226 JPH3_CTG Arina Puzriakova Phenotypes for STR: JPH3_CTG were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Adult onset neurodegenerative disorder v2.225 JPH3_CTG Arina Puzriakova Tag watchlist tag was added to STR: JPH3_CTG.
Early onset dystonia v1.96 JPH3_CTG Arina Puzriakova Phenotypes for STR: JPH3_CTG were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.58 JPH3_CTG Arina Puzriakova Phenotypes for STR: JPH3_CTG were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Parkinson Disease and Complex Parkinsonism v1.82 JPH3_CTG Arina Puzriakova Phenotypes for STR: JPH3_CTG were changed from Huntington disease-like 2 606438 to Huntington disease-like 2, OMIM:606438
Skeletal muscle channelopathy v1.36 DMPK_CTG Arina Puzriakova Tag STR tag was added to STR: DMPK_CTG.
Intellectual disability v3.1433 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Mitochondrial disorders v2.55 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Paediatric motor neuronopathies v1.71 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Likely inborn error of metabolism v2.194 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Congenital myopathy v2.67 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Congenital muscular dystrophy v2.21 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Paroxysmal central nervous system disorders v1.28 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Gastrointestinal neuromuscular disorders v1.18 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Fetal hydrops v1.42 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Skeletal Muscle Channelopathies v1.41 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Fetal anomalies v1.807 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from DYSTROPHIA MYOTONICA TYPE 1 to Myotonic dystrophy 1, OMIM:160900
Fetal anomalies v1.806 DMPK Arina Puzriakova Mode of pathogenicity for gene: DMPK 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
Arthrogryposis v3.142 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Dilated Cardiomyopathy and conduction defects v1.74 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from syndromic DCM to Myotonic dystrophy 1, OMIM:160900
Gastrointestinal neuromuscular disorders v1.17 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Fetal hydrops v1.41 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1, 160900; DM1; Myotonic dystrophy, congenital onset associated with a high triplet repeat number to Myotonic dystrophy 1, OMIM:160900
Congenital myopathy v2.66 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Skeletal muscle channelopathy v1.36 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1, 160900 to Myotonic dystrophy 1, OMIM:160900
Intellectual disability v3.1432 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1, 160900; DYSTROPHIA MYOTONICA TYPE 1 (DM1) to Myotonic dystrophy 1, OMIM:160900
Childhood onset dystonia, chorea or related movement disorder v1.183 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Childhood onset dystonia, chorea or related movement disorder v1.183 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1431 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1431 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
DDG2P v2.53 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism. MOI should be changed to 'Other' to maintain consistency with other panels
DDG2P v2.53 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v2.52 DMPK Arina Puzriakova Tag Q3_21_MOI tag was added to gene: DMPK.
Paediatric motor neuronopathies v1.70 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paediatric motor neuronopathies v1.70 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Fetal anomalies v1.805 DMPK Arina Puzriakova Tag Q3_21_MOI tag was added to gene: DMPK.
Fetal anomalies v1.805 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism. MOI should be changed to 'Other' to maintain consistency with other panels
Fetal anomalies v1.805 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal muscle channelopathy v1.35 DMPK Arina Puzriakova Mode of pathogenicity for gene: DMPK 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
Skeletal muscle channelopathy v1.34 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Skeletal muscle channelopathy v1.34 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Skeletal muscle channelopathy v1.33 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Congenital myopathy v2.65 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Congenital myopathy v2.65 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Arthrogryposis v3.141 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Arthrogryposis v3.141 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Arthrogryposis v3.140 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Paroxysmal central nervous system disorders v1.27 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paroxysmal central nervous system disorders v1.27 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Paroxysmal central nervous system disorders v1.26 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Dilated Cardiomyopathy and conduction defects v1.73 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Dilated Cardiomyopathy and conduction defects v1.73 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Dilated Cardiomyopathy and conduction defects v1.72 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Gastrointestinal neuromuscular disorders v1.16 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Gastrointestinal neuromuscular disorders v1.16 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Gastrointestinal neuromuscular disorders v1.15 DMPK Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: DMPK.
Distal myopathies v1.37 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Distal myopathies v1.37 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Distal myopathies v1.36 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Fetal hydrops v1.40 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Fetal hydrops v1.40 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Skeletal Muscle Channelopathies v1.40 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Skeletal Muscle Channelopathies v1.40 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Adult onset dystonia, chorea or related movement disorder v1.141 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Hereditary ataxia with onset in adulthood v2.109 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
DDG2P v2.52 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Fetal anomalies v1.804 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Likely inborn error of metabolism v2.193 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Undiagnosed metabolic disorders v1.492 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Adult onset neurodegenerative disorder v2.225 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Paroxysmal central nervous system disorders v1.26 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Hereditary ataxia v1.265 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Fetal anomalies v1.804 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from UNVERRICHT-LUNDBORG DISEASE to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Early onset or syndromic epilepsy v2.462 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Intellectual disability v3.1430 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from UNVERRICHT-LUNDBORG DISEASE to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Childhood onset dystonia, chorea or related movement disorder v1.182 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Early onset dystonia v1.95 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A, 254800; microcephaly and severe dyskinesia (26843564) to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Early onset dystonia v1.94 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Childhood onset dystonia, chorea or related movement disorder v1.182 CSTB Arina Puzriakova reviewed gene: CSTB: Rating: ; Mode of pathogenicity: None; Publications: 26843564; Phenotypes: Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) OMIM:254800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.193 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Undiagnosed metabolic disorders v1.492 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Myoclonic epilepsy of Unverricht and Lundborg (Other metabolic disorders); Intellectual disability to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Adult onset neurodegenerative disorder v2.225 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A, 254800; Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800; microcephaly and severe dyskinesia (26843564) to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Paroxysmal central nervous system disorders v1.26 CSTB Arina Puzriakova Mode of inheritance for gene: CSTB was changed from to BIALLELIC, autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v1.25 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Hereditary ataxia v1.265 CSTB Arina Puzriakova Classified gene: CSTB as Green List (high evidence)
Hereditary ataxia v1.265 CSTB Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green as ataxia is a common part of the phenotype. This also reflects the current rating on GMS ataxia panels.
Hereditary ataxia v1.265 CSTB Arina Puzriakova Gene: cstb has been classified as Green List (High Evidence).
Hereditary ataxia v1.264 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Ataxia and cerebellar anomalies - narrow panel v2.260 CSTB Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CSTB.
Hereditary ataxia with onset in adulthood v2.109 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Progressive myoclonic epilepsy 1A, 254800; Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Adult onset dystonia, chorea or related movement disorder v1.141 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from microcephaly and severe dyskinesia (26843564); Epilepsy, progressive myoclonic 1A, 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Childhood onset dystonia, chorea or related movement disorder v1.182 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Adult onset dystonia, chorea or related movement disorder v1.140 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Intellectual disability v3.1429 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Adult onset dystonia, chorea or related movement disorder v1.139 CSTB_CCCCGCCCCGCG Arina Puzriakova Tag watchlist tag was added to STR: CSTB_CCCCGCCCCGCG.
Hereditary ataxia with onset in adulthood v2.108 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Early onset or syndromic epilepsy v2.461 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Adult onset neurodegenerative disorder v2.224 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Adult onset neurodegenerative disorder v2.223 CSTB_CCCCGCCCCGCG Arina Puzriakova Tag watchlist tag was added to STR: CSTB_CCCCGCCCCGCG.
Paroxysmal central nervous system disorders v1.24 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Hereditary ataxia v1.263 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Brain channelopathy v1.66 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Skeletal muscle channelopathy v1.33 CNBP_CCTG Arina Puzriakova commented on STR: CNBP_CCTG
Skeletal muscle channelopathy v1.33 CNBP_CCTG Arina Puzriakova Tag Q4_21_expert_review tag was added to STR: CNBP_CCTG.
Fetal anomalies v1.803 CNBP_CCTG Arina Puzriakova Classified STR: CNBP_CCTG as Red List (low evidence)
Fetal anomalies v1.803 CNBP_CCTG Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to support the gene-disease association but setting rating to Red as currently the performance of the pipeline for this STR is very poor as it is located in a complex locus.
Fetal anomalies v1.803 CNBP_CCTG Arina Puzriakova Str: cnbp_cctg has been classified as Red List (Low Evidence).
Fetal anomalies v1.802 CNBP_CCTG Arina Puzriakova STR: CNBP_CCTG was added
STR: CNBP_CCTG was added to Fetal anomalies. Sources: Expert Review
STR, NGS Not Validated tags were added to STR: CNBP_CCTG.
Mode of inheritance for STR: CNBP_CCTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: CNBP_CCTG were set to Myotonic dystrophy 2, OMIM:602668
Added comment: The mutation is a CCTG repeat expansion in intron 1 of the CNBP (ZNF9) gene. The range of expanded allele sizes is 75 to 11,000 CCTG repeats, whereas normal is up to 30.

The CCTG repeat tract in normal alleles typically contains one or more tetranucleotide interruptions. The sequence interruptions that are routinely found within the CCTG tracts of normal alleles are not found in sequenced pathogenic CCTG expansions of CNBP alleles. On transmission to the next generation, CNBP repeat length sometimes diminishes dramatically, without significant differences determined by the gender of the transmitting parent.
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Copied from Rhiannon Mellis (GOSH) review of gene CNBP on Fetal anomalies panel:

This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.
Sources: Expert Review
Fetal anomalies v1.801 CNBP Arina Puzriakova changed review comment from: Comment on list classification: Demoted to Red, this review is for the STR entity and not the gene entity.; to: Comment on list classification: Demoted to Red, this review is for the STR entity and not the gene entity. STR added separately.
Distal myopathies v1.36 CNBP Arina Puzriakova changed review comment from: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism; to: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism. MOI should be changed to 'Other' to maintain consistency with other panels
Distal myopathies v1.36 CNBP Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CNBP.
Tag Q4_21_rating tag was added to gene: CNBP.
Distal myopathies v1.36 CNBP Arina Puzriakova Classified gene: CNBP as Green List (high evidence)
Distal myopathies v1.36 CNBP Arina Puzriakova Added comment: Comment on list classification: Should be demoted to Red at the next GMS update, this review is for the STR entity and not the gene entity.
Distal myopathies v1.36 CNBP Arina Puzriakova Gene: cnbp has been classified as Green List (High Evidence).
Distal myopathies v1.35 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.801 CNBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CNBP.
Tag currently-ngs-unreportable tag was added to gene: CNBP.
Fetal anomalies v1.801 CNBP Arina Puzriakova Tag for-review was removed from gene: CNBP.
Fetal anomalies v1.801 CNBP Arina Puzriakova Classified gene: CNBP as Red List (low evidence)
Fetal anomalies v1.801 CNBP Arina Puzriakova Added comment: Comment on list classification: Demoted to Red, this review is for the STR entity and not the gene entity.
Fetal anomalies v1.801 CNBP Arina Puzriakova Gene: cnbp has been classified as Red List (Low Evidence).
Fetal anomalies v1.800 CNBP Arina Puzriakova Mode of pathogenicity for gene: CNBP 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
Fetal anomalies v1.799 CNBP Arina Puzriakova Classified gene: CNBP as Red List (low evidence)
Fetal anomalies v1.799 CNBP Arina Puzriakova Gene: cnbp has been classified as Red List (Low Evidence).
Fetal anomalies v1.798 CNBP Arina Puzriakova Phenotypes for gene: CNBP were changed from Myotonic dystrophy 2, 602668 to Myotonic dystrophy 2, OMIM:602668
COVID-19 research v1.81 CNBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: CNBP.
Tag currently-ngs-unreportable tag was added to gene: CNBP.
Mosaic skin disorders - deep sequencing v1.9 PORCN Tom Cullup gene: PORCN was added
gene: PORCN was added to Mosaic skin disorders - deep sequencing. Sources: Other
Mode of inheritance for gene: PORCN 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: PORCN were set to 17546030
Phenotypes for gene: PORCN were set to Focal dermal hypoplasia (https://omim.org/entry/305600)
Penetrance for gene: PORCN were set to unknown
Review for gene: PORCN was set to GREEN
Added comment: Sources: Other
Skeletal muscle channelopathy v1.33 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Skeletal muscle channelopathy v1.33 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Paroxysmal central nervous system disorders v1.23 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paroxysmal central nervous system disorders v1.23 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Primary immunodeficiency or monogenic inflammatory bowel disease v2.485 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Primary immunodeficiency or monogenic inflammatory bowel disease v2.485 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
COVID-19 research v1.81 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
COVID-19 research v1.81 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from Unknown to Other
Fetal anomalies v1.797 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Fetal anomalies v1.797 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Distal myopathies v1.34 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Distal myopathies v1.34 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Skeletal Muscle Channelopathies v1.39 CNBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Skeletal Muscle Channelopathies v1.39 CNBP Arina Puzriakova Mode of inheritance for gene: CNBP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Cholestasis v1.93 FARSA Ivone Leong Classified gene: FARSA as Amber List (moderate evidence)
Cholestasis v1.93 FARSA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber as there is now an additional case (see comment for publication).
Cholestasis v1.93 FARSA Ivone Leong Gene: farsa has been classified as Amber List (Moderate Evidence).
Cholestasis v1.92 FARSA Ivone Leong Added comment: Comment on publications: PMID:33598926 describes one other case with cholestasis
Cholestasis v1.92 FARSA Ivone Leong Publications for gene: FARSA were set to 31355908
Cholestasis v1.91 FARSA Ivone Leong Tag watchlist tag was added to gene: FARSA.
Familial pulmonary fibrosis v1.18 FARSA Ivone Leong Publications for gene: FARSA were set to 31355908
Familial pulmonary fibrosis v1.17 FARSA Ivone Leong Classified gene: FARSA as Green List (high evidence)
Familial pulmonary fibrosis v1.17 FARSA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. There is now enough evidence to support a gene-disease association (>3 cases).
Familial pulmonary fibrosis v1.17 FARSA Ivone Leong Gene: farsa has been classified as Green List (High Evidence).
Intellectual disability v3.1428 FARSA Ivone Leong Tag Q4_21_rating tag was added to gene: FARSA.
Intellectual disability v3.1428 FARSA Ivone Leong Classified gene: FARSA as Amber List (moderate evidence)
Intellectual disability v3.1428 FARSA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. There is now enough evidence to support a gene-disease association (>3 cases). This gene should be rated Green at the next review.
Intellectual disability v3.1428 FARSA Ivone Leong Gene: farsa has been classified as Amber List (Moderate Evidence).
Intracerebral calcification disorders v1.32 FARSA Ivone Leong Publications for gene: FARSA were set to 31355908
Intracerebral calcification disorders v1.31 FARSA Ivone Leong Classified gene: FARSA as Green List (high evidence)
Intracerebral calcification disorders v1.31 FARSA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. There is now enough evidence to support a gene-disease association (>3 cases).
Intracerebral calcification disorders v1.31 FARSA Ivone Leong Gene: farsa has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - narrow panel v1.214 FARSA Ivone Leong Tag Q4_21_rating tag was added to gene: FARSA.
White matter disorders and cerebral calcification - narrow panel v1.214 FARSA Ivone Leong Classified gene: FARSA as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.214 FARSA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. There is now enough evidence to support a gene-disease association (>3 cases). This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.214 FARSA Ivone Leong Gene: farsa has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.213 FARSA Ivone Leong Publications for gene: FARSA were set to 31355908
Familial cerebral small vessel disease v1.11 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Episodic ataxia, type 2 108500; Migraine, familial hemiplegic, 1 141500 AD; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia 141500; Spinocerebellar ataxia 6 183086 to Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Intellectual disability v3.1427 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Epileptic encephalopathy, early infantile, 42 617106; Episodic ataxia, type 2 108500; Migraine, familial hemiplegic, 1 141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia 141500; Spinocerebellar ataxia 6 183086 to Developemental and epileptic encephalopathy 42, OMIM:617106
Early onset or syndromic epilepsy v2.460 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Epileptic encephalopathy, early infantile, 42, 617106; Epilepsy and migraine; Absence epilepsy; Migraine, familial hemiplegic, 1, 141500; Familial hemiplegic migraine 1 (FHM) to Developmental and epileptic encephalopathy 42, OMIM:617106; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Adult onset neurodegenerative disorder v2.223 CACNA1A Arina Puzriakova Added comment: Comment on mode of inheritance: CACNA1A is associated with several phenotypes including SCA6 (OMIM:183086), episodic ataxia (OMIM:108500), familial hemiplegic migraine with or without ataxia (OMIM:141500), or developmental and epileptic encephalopathy (OMIM:617106). SCA6 is the only condition that may align with this panel; however, it is caused by nucleotide repeat expansions and there is a lack of relevance for SNVs.
Adult onset neurodegenerative disorder v2.223 CACNA1A Arina Puzriakova Mode of inheritance for gene: CACNA1A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Congenital myaesthenic syndrome v2.39 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from episodic ataxia plus myasthenic syndrome; hemiplegic migraine plus disturbed NMJ function to Lambert-Eaton myasthenic syndrome, MONDO:0018556
Adult onset neurodegenerative disorder v2.222 CACNA1A Arina Puzriakova Tag treatable was removed from gene: CACNA1A.
Tag currently-ngs-unreportable tag was added to gene: CACNA1A.
Adult onset neurodegenerative disorder v2.222 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from episodic ataxia type 2 (EA2),108500; familial hemiplegic migraine type 1, 141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia; Dystonia; Spinocerebellar ataxia 6; Episodic ataxia, type 2 to Spinocerebellar ataxia 6, OMIM:183086
Paroxysmal central nervous system disorders v1.22 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, 141500; EA2; Migraine, familial hemiplegic, 1, 141500; Episodic Ataxia, Type 2; familial hemiplegic migraine type 1, 141500; episodic ataxia type 2 (EA2),108500; Spinocerebellar ataxia 6, 183086; Episodic ataxia, type 2, 108500 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Albinism or congenital nystagmus v1.20 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from CACNA1A-Related Episodic Ataxia Type 2; Acetazolamide-Responsive Hereditary Paroxysmal Cerebellar Ataxia; Episodic Ataxia Type 2 (EA2) Episodic Ataxia, Nystagmus-Associated to Episodic ataxia, type 2, OMIM:108500
Hereditary ataxia v1.262 CACNA1A Arina Puzriakova Tag nucleotide-repeat-expansion was removed from gene: CACNA1A.
Adult onset dystonia, chorea or related movement disorder v1.139 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Episodic ataxia, type 2, OMIM:108500; Spinocerebellar ataxia 6, OMIM:183086; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Hereditary ataxia with onset in adulthood v2.107 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from SCA6, 183086; familial hemiplegic migraine type 1, 141500; Episodic ataxia, type 2; Spinocerebellar ataxia 6; Familial hemiplegic migraine 1, 141500; Episodic ataxia type 2, 108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia; episodic ataxia type 2 (EA2),108500 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Hereditary ataxia v1.262 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Episodic ataxia, type 2; Spinocerebellar ataxia 6; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Ataxia and cerebellar anomalies - narrow panel v2.260 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia; Spinocerebellar ataxia 6; Episodic ataxia, type 2 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Skeletal muscle channelopathy v1.32 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Episodic ataxia 2 with periodic paralysis; Epileptic encephalopathy, early infantile, 42 OMIM:617106; Migraine, familial hemiplegic, 1 OMIM:141500; Episodic ataxia, type 2 OMIM:108500 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Childhood onset dystonia, chorea or related movement disorder v1.181 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from familial hemiplegic migraine type 1, 141500; Dystonia; episodic ataxia type 2 (EA2), 108500 to Episodic ataxia, type 2, OMIM:108500
Early onset dystonia v1.94 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Dystonia to Episodic ataxia, type 2, OMIM:108500
Early onset dystonia v1.93 CACNA1A Arina Puzriakova Mode of inheritance for gene: CACNA1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain channelopathy v1.65 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from episodic ataxia type 2 (EA2),108500; familial hemiplegic migraine type 1, 141500 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Skeletal Muscle Channelopathies v1.38 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Migraine, familial hemiplegic, 1, 141500; Episodic ataxia, type 2, 108500; Spinocerebellar ataxia 6, 183086; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, 141500; Episodic Ataxia, Type 2; EA2 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Familial Meniere Disease v1.2 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Episodic ataxia type 2; migraine familial hemiplegic type 1 to Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, OMIM:141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Infantile nystagmus v1.4 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from CACNA1A-Related Episodic Ataxia Type 2; Episodic Ataxia Type 2 (EA2) Episodic Ataxia, Nystagmus-Associated; Acetazolamide-Responsive Hereditary Paroxysmal Cerebellar Ataxia to Episodic ataxia, type 2, OMIM:108500
Adult onset dystonia, chorea or related movement disorder v1.138 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Adult onset dystonia, chorea or related movement disorder v1.137 CACNA1A_CAG Arina Puzriakova Tag watchlist tag was added to STR: CACNA1A_CAG.
Hereditary ataxia with onset in adulthood v2.106 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Adult onset neurodegenerative disorder v2.221 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Adult onset neurodegenerative disorder v2.220 CACNA1A_CAG Arina Puzriakova Tag watchlist tag was added to STR: CACNA1A_CAG.
Adult onset hereditary spastic paraplegia v1.78 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Childhood onset hereditary spastic paraplegia v2.92 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Hereditary spastic paraplegia v1.264 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Paroxysmal central nervous system disorders v1.21 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Hereditary ataxia v1.261 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Ataxia and cerebellar anomalies - narrow panel v2.259 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Ataxia and cerebellar anomalies - narrow panel v2.258 CACNA1A_CAG Arina Puzriakova Tag watchlist tag was added to STR: CACNA1A_CAG.
Brain channelopathy v1.64 CACNA1A_CAG Arina Puzriakova Phenotypes for STR: CACNA1A_CAG were changed from Spinocerebellar ataxia 6 183086 to Spinocerebellar ataxia 6, OMIM:183086
Adult onset dystonia, chorea or related movement disorder v1.137 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Intellectual disability v3.1426 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Amyotrophic lateral sclerosis/motor neuron disease v1.46 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Adult onset neurodegenerative disorder v2.220 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.57 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Parkinson Disease and Complex Parkinsonism v1.81 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Childhood onset dystonia, chorea or related movement disorder v1.180 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Parkinson Disease and Complex Parkinsonism v1.80 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from (Hexanucleotideexpansion); clinical presentation suggestive of cortico-basal/PSP syndrome; complex parkinsonism to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Parkinson Disease and Complex Parkinsonism v1.79 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.79 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Parkinson Disease and Complex Parkinsonism v1.78 C9orf72 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: C9orf72.
Intellectual disability v3.1425 C9orf72 Arina Puzriakova Mode of pathogenicity for gene: C9orf72 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
Adult onset dystonia, chorea or related movement disorder v1.136 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset dystonia, chorea or related movement disorder v1.136 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1424 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1424 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Amyotrophic lateral sclerosis/motor neuron disease v1.45 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Amyotrophic lateral sclerosis/motor neuron disease v1.45 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Adult onset neurodegenerative disorder v2.219 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.219 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.56 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.56 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Childhood onset dystonia, chorea or related movement disorder v1.179 C9orf72 Arina Puzriakova commented on gene: C9orf72
Childhood onset dystonia, chorea or related movement disorder v1.179 C9orf72 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: C9orf72.
Childhood onset dystonia, chorea or related movement disorder v1.179 C9orf72 Arina Puzriakova Tag Q2_21_phenotype was removed from gene: C9orf72.
Tag Q2_21_expert_review was removed from gene: C9orf72.
Tag Q4_21_rating tag was added to gene: C9orf72.
Childhood onset dystonia, chorea or related movement disorder v1.179 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Adult onset dystonia, chorea or related movement disorder v1.135 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from complex parkinsonism; (Hexanucleotideexpansion); clinical presentation suggestive of cortico-basal/PSP syndrome to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Intellectual disability v3.1423 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Adult onset dystonia, chorea or related movement disorder v1.134 C9orf72 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: C9orf72.
Tag currently-ngs-unreportable tag was added to gene: C9orf72.
Amyotrophic lateral sclerosis/motor neuron disease v1.44 C9orf72 Arina Puzriakova Publications for gene: C9orf72 were set to PMID: 21944778; 21944779; 25638642; 27059391; 23597494
Amyotrophic lateral sclerosis/motor neuron disease v1.43 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from Amyotrophic Lateral Sclerosis/Frontotemporal Dementia; Amyotrophic lateral sclerosis and/or frontotemporal dementia, 105550 -3; Hexanucleotide repeat expansion; Frontotemporal Dementia, Amyotrophic Lateral Sclerosis; amyotrophic lateral sclerosis; frontotemporal dementia; Frontotemporal Dementia, Amyotrophic Lateral Sclerosis to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Amyotrophic lateral sclerosis/motor neuron disease v1.42 C9orf72 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: C9orf72.
Adult onset neurodegenerative disorder v2.218 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from complex parkinsonism; Amyotrophic Lateral Sclerosis/Frontotemporal Dementia; Amyotrophic lateral sclerosis and/or frontotemporal dementia, 105550 -3; clinical presentation suggestive of cortico-basal/PSP syndrome; (Hexanucleotideexpansion); Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis; Clinical syndrome FTLD (Frontotemporal lobar degeneration); Frontotemporal Dementia, Amyotrophic Lateral Sclerosis; Hexanucleotide repeat expansion; amyotrophic lateral sclerosis; frontotemporal dementia to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.55 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from Amyotrophic lateral sclerosis and/or frontotemporal dementia, 105550 -3; Amyotrophic Lateral Sclerosis/Frontotemporal Dementia; Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis; Clinical syndrome FTLD (Frontotemporal lobar degeneration) to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Fetal anomalies v1.796 MMP15 Ivone Leong Tag watchlist tag was added to gene: MMP15.
Fetal anomalies v1.796 MMP15 Ivone Leong Classified gene: MMP15 as Amber List (moderate evidence)
Fetal anomalies v1.796 MMP15 Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 33875846 describes 3 patients from 2 families with biallelic variants in MMP15 (one is Pro353fs and other is Gly231Arg). One family with 2 affected siblings presented with cholestasis, hepatomegaly, high hepatic transaminases, and congenital heart disease. The other unrelated case showed similar symptoms.

As there are only 2 cases and currently there are no animal models that replicate the human phenotype this gene has been given an Amber rating until more evidence is available.
Fetal anomalies v1.796 MMP15 Ivone Leong Gene: mmp15 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.795 MMP15 Ivone Leong Phenotypes for gene: MMP15 were changed from Cholestasis; congenital heart disease to Cholestasis, MONDO:0001751; congenital heart disease, MONDO:0005453
Fetal anomalies v1.794 MMP15 Ivone Leong Publications for gene: MMP15 were set to PMID: 33875846
Cholestasis v1.91 MMP15 Ivone Leong Tag watchlist tag was added to gene: MMP15.
Cholestasis v1.91 MMP15 Ivone Leong Classified gene: MMP15 as Amber List (moderate evidence)
Cholestasis v1.91 MMP15 Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 33875846 describes 3 patients from 2 families with biallelic variants in MMP15 (one is Pro353fs and other is Gly231Arg). One family with 2 affected siblings presented with cholestasis, hepatomegaly, high hepatic transaminases, and congenital heart disease. The other unrelated case showed similar symptoms.

As there are only 2 cases and currently there are no animal models that replicate the human phenotype this gene has been given an Amber rating until more evidence is available.
Cholestasis v1.91 MMP15 Ivone Leong Gene: mmp15 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.90 MMP15 Ivone Leong Phenotypes for gene: MMP15 were changed from Cholestasis; congenital heart disease to Cholestasis, MONDO:0001751; congenital heart disease, MONDO:0005453
Cholestasis v1.89 MMP15 Ivone Leong Publications for gene: MMP15 were set to PMID: 33875846
Retinal disorders v2.233 ATXN7 Arina Puzriakova Mode of pathogenicity for gene: ATXN7 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
Retinal disorders v2.232 ATXN7 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN7.
Tag currently-ngs-unreportable tag was added to gene: ATXN7.
Intellectual disability v3.1422 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary ataxia with onset in adulthood v2.105 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary neuropathy v1.422 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500; Adult onset, cerebellar ataxia, pigmentary macular degeneration, sensory-motor axonal neuropathy to Spinocerebellar ataxia 7, OMIM:164500
Undiagnosed metabolic disorders v1.491 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Adult onset neurodegenerative disorder v2.217 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Adult onset neurodegenerative disorder v2.216 ATXN7_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN7_CAG.
Adult onset hereditary spastic paraplegia v1.77 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Childhood onset hereditary spastic paraplegia v2.91 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary spastic paraplegia v1.263 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary ataxia v1.260 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Ataxia and cerebellar anomalies - narrow panel v2.258 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Retinal disorders v2.232 ATXN7 Arina Puzriakova Classified gene: ATXN7 as Red List (low evidence)
Retinal disorders v2.232 ATXN7 Arina Puzriakova Gene: atxn7 has been classified as Red List (Low Evidence).
Retinal disorders v2.231 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Retinal disorders v2.231 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from to Other
Retinal disorders v2.230 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from to Spinocerebellar ataxia 7, OMIM:164500
Intellectual disability v3.1421 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Likely inborn error of metabolism v2.192 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellar ataxia 7 164500; Spinocerebellar ataxia-7 (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Spinocerebellar ataxia 7, OMIM:164500; Mitochondrial respiratory chain disorders (caused by nuclear variants only)
Childhood onset dystonia, chorea or related movement disorder v1.178 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellar ataxia 7, 164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary ataxia with onset in adulthood v2.104 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellarataxia 7,164500; Spinocerebellar ataxia 7, 164500 to Spinocerebellar ataxia 7, OMIM:164500
Undiagnosed metabolic disorders v1.490 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellar ataxia-7 (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Adult onset neurodegenerative disorder v2.216 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellarataxia7,164500 to Spinocerebellar ataxia 7, OMIM:164500
Hereditary ataxia v1.259 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellarataxia7,164500 to Spinocerebellar ataxia 7, OMIM:164500
Ataxia and cerebellar anomalies - narrow panel v2.257 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellarataxia7,164500 to Spinocerebellar ataxia 7, OMIM:164500
Childhood onset dystonia, chorea or related movement disorder v1.177 ATXN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN1.
Tag currently-ngs-unreportable tag was added to gene: ATXN1.
Childhood onset dystonia, chorea or related movement disorder v1.177 ATXN1 Arina Puzriakova Classified gene: ATXN1 as Red List (low evidence)
Childhood onset dystonia, chorea or related movement disorder v1.177 ATXN1 Arina Puzriakova Gene: atxn1 has been classified as Red List (Low Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.176 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Childhood onset dystonia, chorea or related movement disorder v1.176 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Childhood onset dystonia, chorea or related movement disorder v1.175 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Childhood onset dystonia, chorea or related movement disorder v1.175 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Childhood onset dystonia, chorea or related movement disorder v1.174 ATXN7 Arina Puzriakova Classified gene: ATXN7 as Red List (low evidence)
Childhood onset dystonia, chorea or related movement disorder v1.174 ATXN7 Arina Puzriakova Gene: atxn7 has been classified as Red List (Low Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.173 ATXN7 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN7.
Tag currently-ngs-unreportable tag was added to gene: ATXN7.
Intellectual disability v3.1420 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1420 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Likely inborn error of metabolism v2.191 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Likely inborn error of metabolism v2.191 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Hereditary ataxia with onset in adulthood v2.103 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia with onset in adulthood v2.103 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from Unknown to Other
Likely inborn error of metabolism v2.190 ATXN7 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN7.
Tag currently-ngs-unreportable tag was added to gene: ATXN7.
Undiagnosed metabolic disorders v1.489 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Undiagnosed metabolic disorders v1.489 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Adult onset neurodegenerative disorder v2.215 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.215 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from Unknown to Other
Hereditary ataxia v1.258 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.258 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from to Other
Ataxia and cerebellar anomalies - narrow panel v2.256 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - narrow panel v2.256 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from Unknown to Other
Ataxia and cerebellar anomalies - narrow panel v2.255 ATXN7 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN7.
Tag currently-ngs-unreportable tag was added to gene: ATXN7.
Adult onset dystonia, chorea or related movement disorder v1.134 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Adult onset dystonia, chorea or related movement disorder v1.133 ATXN3_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN3_CAG.
Hereditary ataxia with onset in adulthood v2.102 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Hereditary neuropathy v1.421 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Intellectual disability v3.1419 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Adult onset neurodegenerative disorder v2.214 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Adult onset neurodegenerative disorder v2.213 ATXN3_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN3_CAG.
Adult onset hereditary spastic paraplegia v1.76 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Childhood onset hereditary spastic paraplegia v2.90 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Hereditary spastic paraplegia v1.262 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Hereditary ataxia v1.257 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Ataxia and cerebellar anomalies - narrow panel v2.255 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Ataxia and cerebellar anomalies - narrow panel v2.254 ATXN3_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN3_CAG.
Early onset dystonia v1.92 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Parkinson Disease and Complex Parkinsonism v1.78 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Intellectual disability v3.1418 ATXN3 Arina Puzriakova Mode of pathogenicity for gene: ATXN3 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
Adult onset dystonia, chorea or related movement disorder v1.133 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset dystonia, chorea or related movement disorder v1.133 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Hereditary ataxia with onset in adulthood v2.101 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia with onset in adulthood v2.101 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from Unknown to Other
Adult onset neurodegenerative disorder v2.213 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.213 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Hereditary ataxia v1.256 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.256 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from to Other
Intellectual disability v3.1417 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1417 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Ataxia and cerebellar anomalies - narrow panel v2.254 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - narrow panel v2.254 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from Unknown to Other
Parkinson Disease and Complex Parkinsonism v1.77 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.77 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1416 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Adult onset dystonia, chorea or related movement disorder v1.132 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from (CAGexpansion); familial parkinsonism to Machado-Joseph disease, OMIM:109150
Adult onset dystonia, chorea or related movement disorder v1.131 ATXN3 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN3.
Tag currently-ngs-unreportable tag was added to gene: ATXN3.
Hereditary ataxia with onset in adulthood v2.100 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from Machado-Joseph disease, 109150 to Machado-Joseph disease, OMIM:109150
Intellectual disability v3.1415 ATXN3 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN3.
Adult onset neurodegenerative disorder v2.212 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from familial parkinsonism; (CAGexpansion) to Machado-Joseph disease, OMIM:109150; Susceptibility to Late-Onset Parkinson Disease
Hereditary ataxia v1.255 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from to Machado-Joseph disease, OMIM:109150
Ataxia and cerebellar anomalies - narrow panel v2.253 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from to Machado-Joseph disease, OMIM:109150
Ataxia and cerebellar anomalies - narrow panel v2.252 ATXN3 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN3.
Tag currently-ngs-unreportable tag was added to gene: ATXN3.
Parkinson Disease and Complex Parkinsonism v1.76 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from (CAGexpansion); familial parkinsonism to Machado-Joseph disease, OMIM:109150; Susceptibility to Late-Onset Parkinson Disease
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 TARS Alan Lehmann reviewed gene: TARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 CARS Alan Lehmann reviewed gene: CARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1415 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 MARS Alan Lehmann reviewed gene: MARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia v1.261 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 AARS Alan Lehmann reviewed gene: AARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy v1.420 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Adult onset hereditary spastic paraplegia v1.75 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Childhood onset hereditary spastic paraplegia v2.89 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Ataxia and cerebellar anomalies - narrow panel v2.252 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090
Amyotrophic lateral sclerosis/motor neuron disease v1.42 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Adult onset neurodegenerative disorder v2.211 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Adult onset neurodegenerative disorder v2.210 ATXN2_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN2_CAG.
Hereditary ataxia v1.254 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090
Hereditary ataxia with onset in adulthood v2.99 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090
Adult onset dystonia, chorea or related movement disorder v1.131 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Adult onset dystonia, chorea or related movement disorder v1.130 ATXN2_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN2_CAG.
Childhood onset dystonia, chorea or related movement disorder v1.173 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2, 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Early onset dystonia v1.91 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.54 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Parkinson Disease and Complex Parkinsonism v1.75 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Intellectual disability v3.1414 ATXN2 Arina Puzriakova Mode of pathogenicity for gene: ATXN2 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
Adult onset neurodegenerative disorder v2.210 ATXN2 Arina Puzriakova Mode of pathogenicity for gene: ATXN2 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
Adult onset dystonia, chorea or related movement disorder v1.130 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset dystonia, chorea or related movement disorder v1.130 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Hereditary ataxia with onset in adulthood v2.98 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia with onset in adulthood v2.98 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from Unknown to Other
Intellectual disability v3.1413 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1413 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Amyotrophic lateral sclerosis/motor neuron disease v1.41 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Amyotrophic lateral sclerosis/motor neuron disease v1.41 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from to Other
Hereditary ataxia v1.253 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.253 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from to Other
Ataxia and cerebellar anomalies - narrow panel v2.251 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - narrow panel v2.251 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from Unknown to Other
Adult onset neurodegenerative disorder v2.209 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.209 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Ataxia and cerebellar anomalies - narrow panel v2.250 ATXN2 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN2.
Tag currently-ngs-unreportable tag was added to gene: ATXN2.
Hereditary ataxia with onset in adulthood v2.97 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellarataxia2, 183090; Spinocerebellar ataxia 2, 183090; {Amyotrophiclateralsclerosis,susceptibilityto,13},183090 to Spinocerebellar ataxia 2, OMIM:183090
Adult onset dystonia, chorea or related movement disorder v1.129 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from {Parkinson disease, late-onset, susceptibility to}, 168600; (CAGexpansion); familial parkinsonism; Spinocerebellar ataxia 2, 183190; {Amyotrophic lateral sclerosis, susceptibility to, 13}, 183190 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Adult onset dystonia, chorea or related movement disorder v1.128 ATXN2 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN2.
Tag currently-ngs-unreportable tag was added to gene: ATXN2.
Intellectual disability v3.1412 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellar ataxia 2 183090; {Amyotrophic lateral sclerosis, susceptibility to, 13} 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Intellectual disability v3.1411 ATXN2 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN2.
Amyotrophic lateral sclerosis/motor neuron disease v1.40 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellar ataxia 2, 183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, 183090 to {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090
Amyotrophic lateral sclerosis/motor neuron disease v1.39 ATXN2 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN2.
Hereditary ataxia v1.252 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellarataxia2,183090{Amyotrophiclateralsclerosis,susceptibilityto,13},183090 to Spinocerebellar ataxia 2, OMIM:183090
Ataxia and cerebellar anomalies - narrow panel v2.250 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellarataxia2,183090{Amyotrophiclateralsclerosis,susceptibilityto,13},183090 to Spinocerebellar ataxia 2, OMIM:183090
Adult onset neurodegenerative disorder v2.208 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellar ataxia 2, 183090; familial parkinsonism; {Amyotrophic lateral sclerosis, susceptibility to, 13}, 183090; Spinocerebellarataxia2,183090{Amyotrophiclateralsclerosis,susceptibilityto,13},183090; (CAGexpansion) to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Parkinson Disease and Complex Parkinsonism v1.74 ATXN2 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN2.
Parkinson Disease and Complex Parkinsonism v1.74 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Parkinson Disease and Complex Parkinsonism v1.74 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Parkinson Disease and Complex Parkinsonism v1.73 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from (CAGexpansion); familial parkinsonism to {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Intellectual disability v3.1411 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Hereditary ataxia with onset in adulthood v2.96 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Hereditary neuropathy v1.419 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Adult onset neurodegenerative disorder v2.207 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Adult onset neurodegenerative disorder v2.206 ATXN10_ATTCT Arina Puzriakova Tag watchlist tag was added to STR: ATXN10_ATTCT.
Adult onset hereditary spastic paraplegia v1.74 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Adult onset hereditary spastic paraplegia v1.73 ATXN10_ATTCT Arina Puzriakova Tag watchlist tag was added to STR: ATXN10_ATTCT.
Skeletal dysplasia v2.151 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Childhood onset hereditary spastic paraplegia v2.88 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Hereditary spastic paraplegia v1.260 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Hereditary ataxia v1.251 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Thoracic dystrophies v1.15 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Ataxia and cerebellar anomalies - narrow panel v2.249 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Ataxia and cerebellar anomalies - narrow panel v2.248 ATXN10_ATTCT Arina Puzriakova Tag watchlist tag was added to STR: ATXN10_ATTCT.
Early onset dystonia v1.90 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.53 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Childhood onset dystonia, chorea or related movement disorder v1.172 ATXN10 Arina Puzriakova Mode of pathogenicity for gene: ATXN10 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
Childhood onset dystonia, chorea or related movement disorder v1.171 ATXN10 Arina Puzriakova Classified gene: ATXN10 as Red List (low evidence)
Childhood onset dystonia, chorea or related movement disorder v1.171 ATXN10 Arina Puzriakova Gene: atxn10 has been classified as Red List (Low Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.170 ATXN10 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN10.
Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Rare multisystem ciliopathy disorders v1.151 ATXN10 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Adult onset neurodegenerative disorder v2.206 ATXN10 Arina Puzriakova Tag watchlist was removed from gene: ATXN10.
Skeletal dysplasia v2.150 ATXN10 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Primary ciliary disorders v1.35 ATXN10 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Hereditary ataxia v1.250 ATXN10 Arina Puzriakova Tag watchlist was removed from gene: ATXN10.
Thoracic dystrophies v1.14 ATXN10 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Ataxia and cerebellar anomalies - narrow panel v2.248 ATXN10 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN10.
Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Childhood onset dystonia, chorea or related movement disorder v1.170 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Childhood onset dystonia, chorea or related movement disorder v1.170 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1410 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1410 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Rare multisystem ciliopathy disorders v1.151 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Rare multisystem ciliopathy disorders v1.151 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from to Other
Hereditary ataxia with onset in adulthood v2.95 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia with onset in adulthood v2.95 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from Unknown to Other
Skeletal dysplasia v2.150 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Skeletal dysplasia v2.150 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from to Other
Adult onset neurodegenerative disorder v2.206 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.206 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from Unknown to Other
Primary ciliary disorders v1.35 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Primary ciliary disorders v1.35 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from to Other
Hereditary ataxia v1.250 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.250 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from to Other
Thoracic dystrophies v1.14 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Thoracic dystrophies v1.14 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from to Other
Ataxia and cerebellar anomalies - narrow panel v2.248 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - narrow panel v2.248 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from Unknown to Other
Childhood onset dystonia, chorea or related movement disorder v1.169 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellar ataxia 10, 603516 to Spinocerebellar ataxia 10, OMIM:603516
Rare multisystem ciliopathy disorders v1.150 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellar ataxia 10, 603516; Ciliopathies to Spinocerebellar ataxia 10, OMIM:603516; Ciliopathies
Hereditary ataxia with onset in adulthood v2.94 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellar ataxia 10, 603516; Spinocerebellarataxia10, 603516 to Spinocerebellar ataxia 10, OMIM:603516
Intellectual disability v3.1409 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Adult onset neurodegenerative disorder v2.205 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellarataxia10,603516 to Spinocerebellar ataxia 10, OMIM:603516
Skeletal dysplasia v2.149 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from to Spinocerebellar ataxia 10, OMIM:603516
Primary ciliary disorders v1.34 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from ciliopathies to Spinocerebellar ataxia 10, OMIM:603516; Ciliopathies
Hereditary ataxia v1.249 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellarataxia10,603516 to Spinocerebellar ataxia 10, OMIM:603516
Thoracic dystrophies v1.13 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from to Spinocerebellar ataxia 10, OMIM:603516
Ataxia and cerebellar anomalies - narrow panel v2.247 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellarataxia10,603516 to Spinocerebellar ataxia 10, OMIM:603516
Ataxia and cerebellar anomalies - narrow panel v2.246 ATN1_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATN1_CAG.
Adult onset dystonia, chorea or related movement disorder v1.128 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Hereditary ataxia with onset in adulthood v2.93 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Early onset or syndromic epilepsy v2.459 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Adult onset neurodegenerative disorder v2.204 ATN1_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATN1_CAG.
Adult onset neurodegenerative disorder v2.204 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Paroxysmal central nervous system disorders v1.20 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Hereditary ataxia v1.248 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Ataxia and cerebellar anomalies - narrow panel v2.246 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Brain channelopathy v1.63 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.52 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Parkinson Disease and Complex Parkinsonism v1.72 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Adult onset neurodegenerative disorder v2.203 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Paroxysmal central nervous system disorders v1.19 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy, 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Brain channelopathy v1.62 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.51 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Hereditary ataxia v1.247 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Ataxia and cerebellar anomalies - narrow panel v2.245 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Childhood onset dystonia, chorea or related movement disorder v1.168 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Childhood onset dystonia, chorea or related movement disorder v1.168 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Childhood onset dystonia, chorea or related movement disorder v1.167 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy, 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Childhood onset dystonia, chorea or related movement disorder v1.166 ATN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATN1.
Tag currently-ngs-unreportable tag was added to gene: ATN1.
Adult onset dystonia, chorea or related movement disorder v1.127 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Hereditary ataxia with onset in adulthood v2.92 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Dentato-pallidoluysian atrophy; Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Adult onset dystonia, chorea or related movement disorder v1.126 ATN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATN1.
Tag currently-ngs-unreportable tag was added to gene: ATN1.
Adult onset dystonia, chorea or related movement disorder v1.126 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset dystonia, chorea or related movement disorder v1.126 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Hereditary ataxia with onset in adulthood v2.91 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia with onset in adulthood v2.91 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Hereditary ataxia v1.246 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Hereditary ataxia v1.246 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from Other - please specifiy in evaluation comments to Other
Ataxia and cerebellar anomalies - narrow panel v2.244 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Ataxia and cerebellar anomalies - narrow panel v2.244 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from Other - please specifiy in evaluation comments to Other
DDG2P v2.52 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from congenital hypotonia, epilepsy, developmental delay, digit abnormalities to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, OMIM:618494
Paroxysmal central nervous system disorders v1.18 ATN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATN1.
Tag currently-ngs-unreportable tag was added to gene: ATN1.
Ataxia and cerebellar anomalies - narrow panel v2.243 ATN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATN1.
Tag currently-ngs-unreportable tag was added to gene: ATN1.
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.50 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.50 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Brain channelopathy v1.61 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Brain channelopathy v1.61 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Paroxysmal central nervous system disorders v1.18 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Paroxysmal central nervous system disorders v1.18 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Adult onset neurodegenerative disorder v2.202 ATN1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Nucleotide repeat expansion; to: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Adult onset neurodegenerative disorder v2.202 ATN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Nucleotide repeat expansion
Adult onset neurodegenerative disorder v2.202 ATN1 Arina Puzriakova Mode of inheritance for gene: ATN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Intellectual disability v3.1408 ATN1 Arina Puzriakova Publications for gene: ATN1 were set to 24972706; 30827498
Intellectual disability v3.1407 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Feeding difficulties; Abnormality of the cardiovascular system; Cleft palate; Abnormality of the kidney to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, OMIM:618494
Early onset or syndromic epilepsy v2.458 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures; Generalized hypotonia to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, OMIM:618494
Primary immunodeficiency or monogenic inflammatory bowel disease v2.484 ZNFX1 Sophie Hambleton reviewed gene: ZNFX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Haematological malignancies cancer susceptibility v2.21 RPS27A Arina Puzriakova Tag pharmacogenetic was removed from gene: RPS27A.
Tag pharmacogenetics tag was added to gene: RPS27A.
Sarcoma cancer susceptibility v1.20 T Arina Puzriakova Tag cnvs was removed from gene: T.
Tag cnv tag was added to gene: T.
Intellectual disability v3.1406 KIDINS220 Dmitrijs Rots reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33763417; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary spastic paraplegia v1.259 KIDINS220 Dmitrijs Rots reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33763417; Phenotypes: Spastic paraplegia, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1406 VAMP7 Ivone Leong Tag Pseudoautosomal region 2 tag was added to gene: VAMP7.
Intellectual disability v3.1406 SPRY3 Ivone Leong Tag Pseudoautosomal region 2 tag was added to gene: SPRY3.
Intellectual disability v3.1406 SLC25A6 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SLC25A6.
Skeletal dysplasia v2.148 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Limb disorders v2.65 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
IUGR and IGF abnormalities v1.41 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Radial dysplasia v1.15 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Fetal anomalies v1.793 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Osteogenesis imperfecta v2.37 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
DDG2P v2.51 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Intellectual disability v3.1406 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Intellectual disability v3.1406 PLCXD1 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: PLCXD1.
Intellectual disability v3.1406 P2RY8 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: P2RY8.
Intellectual disability v3.1406 IL3RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: IL3RA.
Intellectual disability v3.1406 DHRSX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: DHRSX.
Intellectual disability v3.1406 CSF2RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.484 CSF2RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
Familial pulmonary fibrosis v1.16 CSF2RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
COVID-19 research v1.80 CSF2RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
Intellectual disability v3.1406 CRLF2 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CRLF2.
Intellectual disability v3.1406 CD99 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CD99.
Intellectual disability v3.1406 ASMTL Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: ASMTL.
Intellectual disability v3.1406 ASMT Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: ASMT.
Intellectual disability v3.1406 AKAP17A Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: AKAP17A.
Fetal anomalies v1.793 RFT1 Ivone Leong Tag for-reivew was removed from gene: RFT1.
Fetal anomalies v1.793 RFT1 Ivone Leong Tag for-review tag was added to gene: RFT1.
Intellectual disability v3.1406 NUP85 Eleanor Williams Classified gene: NUP85 as Amber List (moderate evidence)
Intellectual disability v3.1406 NUP85 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 2 cases reported but degree of ID not confirmed in the second family.
Intellectual disability v3.1406 NUP85 Eleanor Williams Gene: nup85 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1405 NUP85 Eleanor Williams changed review comment from: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from the 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro), which segregated from the maternal and the paternal side.
Sources: Literature; to: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction.

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro) in NUP85.
Sources: Literature
Intellectual disability v3.1405 NUP85 Eleanor Williams gene: NUP85 was added
gene: NUP85 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NUP85 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP85 were set to 34170319
Phenotypes for gene: NUP85 were set to Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH-SCKS)
Review for gene: NUP85 was set to AMBER
Added comment: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from the 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro), which segregated from the maternal and the paternal side.
Sources: Literature
DDG2P v2.51 EDNRB Ivone Leong Tag Q4_21_MOI tag was added to gene: EDNRB.
DDG2P v2.51 EDNRB Ivone Leong Publications for gene: EDNRB were set to 7778600
DDG2P v2.50 EDNRB Ivone Leong reviewed gene: EDNRB: Rating: ; Mode of pathogenicity: None; Publications: 7778600, 11891690; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v1.18 EDNRB Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" as patients with biallelic variants have a more severe phenotype. This MOI change does not affect tiering.
Pigmentary skin disorders v1.18 EDNRB Ivone Leong Mode of inheritance for gene: EDNRB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Monogenic hearing loss v2.209 EDNRB Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" as patients with biallelic variants have a more severe phenotype. This MOI change does not affect tiering.
Monogenic hearing loss v2.209 EDNRB Ivone Leong Mode of inheritance for gene: EDNRB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Fetal anomalies v1.793 EDNRB Ivone Leong Publications for gene: EDNRB were set to
Fetal anomalies v1.792 EDNRB Ivone Leong reviewed gene: EDNRB: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.792 EDNRB Ivone Leong Tag Q4_21_MOI tag was added to gene: EDNRB.
Fetal anomalies v1.792 SMARCE1 Arina Puzriakova Classified gene: SMARCE1 as Amber List (moderate evidence)
Fetal anomalies v1.792 SMARCE1 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.792 SMARCE1 Arina Puzriakova Gene: smarce1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.791 SMARCE1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: SMARCE1.
Skeletal dysplasia v2.148 SMARCE1 Arina Puzriakova Mode of inheritance for gene: SMARCE1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.147 SMARCE1 Arina Puzriakova Phenotypes for gene: SMARCE1 were changed from Coffin-Siris syndrome to Coffin-Siris syndrome 5, OMIM:616938
Familial Tumours Syndromes of the central & peripheral Nervous system v1.11 SMARCE1 Arina Puzriakova Phenotypes for gene: SMARCE1 were changed from familial spinal and cranial meningiomas to {Meningioma, familial, susceptibility to}, OMIM:607174
Fetal anomalies v1.791 SMARCE1 Arina Puzriakova Publications for gene: SMARCE1 were set to
Fetal anomalies v1.790 SMARCE1 Arina Puzriakova Phenotypes for gene: SMARCE1 were changed from COFFIN SIRIS to Coffin-Siris syndrome 5, OMIM:616938
Primary immunodeficiency or monogenic inflammatory bowel disease v2.484 CXCR2 Sophie Hambleton reviewed gene: CXCR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Monogenic hearing loss v2.208 EDN3 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" as patients with biallelic variants have a more severe phenotype. This MOI change does not affect tiering.
Monogenic hearing loss v2.208 EDN3 Ivone Leong Mode of inheritance for gene: EDN3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Pigmentary skin disorders v1.17 EDN3 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" as patients with biallelic variants have a more severe phenotype. This MOI change does not affect tiering.
Pigmentary skin disorders v1.17 EDN3 Ivone Leong Mode of inheritance for gene: EDN3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Arthrogryposis v3.140 SLC6A9 Arina Puzriakova Classified gene: SLC6A9 as Amber List (moderate evidence)
Arthrogryposis v3.140 SLC6A9 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Arthrogryposis v3.140 SLC6A9 Arina Puzriakova Gene: slc6a9 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.789 SLC6A9 Arina Puzriakova Classified gene: SLC6A9 as Amber List (moderate evidence)
Fetal anomalies v1.789 SLC6A9 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.789 SLC6A9 Arina Puzriakova Gene: slc6a9 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.139 SLC6A9 Arina Puzriakova Publications for gene: SLC6A9 were set to 27773429; 27481395
Fetal anomalies v1.788 SLC6A9 Arina Puzriakova Publications for gene: SLC6A9 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.484 CTNNBL1 Sophie Hambleton reviewed gene: CTNNBL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v3.138 SLC6A9 Arina Puzriakova Phenotypes for gene: SLC6A9 were changed from Glycine encephalopathy with normal serum glycine, 617301; Glycine Encephalopathy with Arthrogryposis to Glycine encephalopathy with normal serum glycine, OMIM:617301
Fetal anomalies v1.787 SLC6A9 Arina Puzriakova Phenotypes for gene: SLC6A9 were changed from Glycine Encephalopathy with Arthrogryposis to Glycine encephalopathy with normal serum glycine, OMIM:617301; Arthrogryposis, MONDO:0008779
Fetal anomalies v1.786 SLC6A9 Arina Puzriakova Tag Q4_21_rating tag was added to gene: SLC6A9.
Arthrogryposis v3.137 SLC6A9 Arina Puzriakova Tag Q4_21_rating tag was added to gene: SLC6A9.
Intellectual disability v3.1404 SLC6A9 Arina Puzriakova Phenotypes for gene: SLC6A9 were changed from Glycine encephalopathy with normal serum glycine, 617301; Glycine encephalopathy and global developmental delay to Glycine encephalopathy with normal serum glycine, OMIM:617301
Fetal anomalies v1.786 PRRX1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: PRRX1.
Fetal anomalies v1.786 PRRX1 Arina Puzriakova Classified gene: PRRX1 as Amber List (moderate evidence)
Fetal anomalies v1.786 PRRX1 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.786 PRRX1 Arina Puzriakova Gene: prrx1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.785 PRRX1 Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' for now as 3 unrelated cases of otocephaly with private heterozygous LoF variants have been reported in literature to date, but only one patient with a homozygous alteration. May be reviewed if evidence of further cases emerges.
Fetal anomalies v1.785 PRRX1 Arina Puzriakova Mode of inheritance for gene: PRRX1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.207 PRRX1 Arina Puzriakova Phenotypes for gene: PRRX1 were changed from to Agnathia-otocephaly complex, OMIM:202650
Fetal anomalies v1.784 PRRX1 Arina Puzriakova Phenotypes for gene: PRRX1 were changed from Agnathia-otocephaly complex to Agnathia-otocephaly complex, OMIM:202650
Fetal anomalies v1.783 PRIM1 Arina Puzriakova Classified gene: PRIM1 as Amber List (moderate evidence)
Fetal anomalies v1.783 PRIM1 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.783 PRIM1 Arina Puzriakova Gene: prim1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.782 PRIM1 Arina Puzriakova Publications for gene: PRIM1 were set to PMID: 33060134
Fetal anomalies v1.781 PRIM1 Arina Puzriakova Phenotypes for gene: PRIM1 were changed from Primordial dwarfism to Microcephalic primordial dwarfism, MONDO:0017950
Fetal anomalies v1.780 PRIM1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: PRIM1.
Fetal anomalies v1.780 POLR1B Arina Puzriakova Publications for gene: POLR1B were set to PMID: 31649276
Fetal anomalies v1.779 POLR1B Arina Puzriakova Phenotypes for gene: POLR1B were changed from Treacher-Collins syndrome 4 to Treacher-Collins syndrome 4 OMIM:618939
Fetal anomalies v1.778 POLR1B Arina Puzriakova Classified gene: POLR1B as Amber List (moderate evidence)
Fetal anomalies v1.778 POLR1B Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.778 POLR1B Arina Puzriakova Gene: polr1b has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.777 POLR1B Arina Puzriakova Tag Q4_21_rating tag was added to gene: POLR1B.
Fetal anomalies v1.777 MN1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: MN1.
Intellectual disability v3.1403 CLPB Ivone Leong Phenotypes for gene: CLPB were changed from 3-METHYLGLUTACONIC ACIDURIA, TYPE VII, WITH CATARACTS, NEUROLOGIC INVOLVEMENT AND NEUTROPENIA to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Early onset or syndromic epilepsy v2.457 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from {Lipodystrophy, partial, acquired, susceptibility to}, 608709; ?Epilepsy, progressive myoclonic, 9, 616540 to ?Epilepsy, progressive myoclonic, 9, OMIM:616540
Intellectual disability v3.1402 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability to Microcephaly 27, primary, autosomal dominant, OMIM:619180
Severe microcephaly v2.270 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability to Microcephaly 27, primary, autosomal dominant, OMIM:619180
Early onset or syndromic epilepsy v2.456 GNB2 Eleanor Williams Entity copied from Mosaic skin disorders - deep sequencing v1.9
Early onset or syndromic epilepsy v2.456 GNB2 Eleanor Williams gene: GNB2 was added
gene: GNB2 was added to Genetic epilepsy syndromes. Sources: Literature
somatic tags were added to gene: GNB2.
Mode of inheritance for gene: GNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GNB2 were set to 34124757
Phenotypes for gene: GNB2 were set to Sturge-Weber syndrome, somatic, mosaic, OMIM:185300
Early onset or syndromic epilepsy v2.455 GNAQ Eleanor Williams Tag mosaicism tag was added to gene: GNAQ.
Tag somatic tag was added to gene: GNAQ.
Early onset or syndromic epilepsy v2.455 GNAQ Eleanor Williams Phenotypes for gene: GNAQ were changed from Sturge-Weber syndrome, somatic, mosaic, 185300 to Sturge-Weber syndrome, somatic, mosaic, OMIM:185300
Early onset or syndromic epilepsy v2.454 GNAQ Eleanor Williams Publications for gene: GNAQ were set to 25374402; 23656586; 28126187
Early onset or syndromic epilepsy v2.453 GNAQ Eleanor Williams reviewed gene: GNAQ: Rating: ; Mode of pathogenicity: None; Publications: 34124757; Phenotypes: Sturge-Weber syndrome, somatic, mosaic, OMIM:185300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mosaic skin disorders - deep sequencing v1.9 GNB2 Eleanor Williams gene: GNB2 was added
gene: GNB2 was added to Mosaic skin disorders - deep sequencing. Sources: Literature
somatic tags were added to gene: GNB2.
Mode of inheritance for gene: GNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GNB2 were set to 34124757
Phenotypes for gene: GNB2 were set to Sturge-Weber syndrome, somatic, mosaic, OMIM:185300
Review for gene: GNB2 was set to RED
Added comment: PMID: 34124757 Fjaer et al 2021 report 1 case of a patient with phenotypic features of Sturge–Weber syndrome (skin legion on left eyelid, nose and brow, mild intellectual disability, refractory eplipsy, left-sided leptomeningeal vascular malformation and atrophy, no eye abnormality) and a variant in GNB2 (NM_005273.3):c.232A>G:p.Lys78Glu, which was present in 6% of the reads from the lesional dermis and 21% of the reads in an endothelial culture from the biopsy, but only present at 0.15% of the reads in non-lesional dermis. The patient was negative for the GNAQ R183Q variant more frequently associated with Sturge–Weber syndrome.
Sources: Literature
Fetal anomalies v1.777 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from Microcephaly 27, primary, autosomal dominant to Microcephaly 27, primary, autosomal dominant, OMIM:619180
Fetal anomalies v1.776 LMNB2 Arina Puzriakova Publications for gene: LMNB2 were set to PMID: 33033404
Fetal anomalies v1.775 LMNB2 Arina Puzriakova Classified gene: LMNB2 as Amber List (moderate evidence)
Fetal anomalies v1.775 LMNB2 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.775 LMNB2 Arina Puzriakova Gene: lmnb2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.774 LMNB2 Arina Puzriakova Tag Q4_21_rating tag was added to gene: LMNB2.
Fetal anomalies v1.774 LMNB1 Arina Puzriakova Publications for gene: LMNB1 were set to PMID: 33033404
Fetal anomalies v1.773 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Microcephaly 26, primary, autosomal dominant to Microcephaly 26, primary, autosomal dominant, OMIM:619179
White matter disorders and cerebral calcification - narrow panel v1.212 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Leukodystrophy,adult-onset, autosomal dominant,169500; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Adult onset autosomal dominant leukodystrophy (ADLD) to Leukodystrophy, adult-onset, autosomal dominant, OMIM:169500
Adult onset leukodystrophy v1.33 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Leukodystrophy, adult-onset, autosomal dominant, 169500 to Leukodystrophy, adult-onset, autosomal dominant, OMIM:169500
Inherited white matter disorders v1.145 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Leukodystrophy,adult-onset, autosomal dominant,169500; Adult onset autosomal dominant leukodystrophy (ADLD); General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukodystrophy, adult-onset, autosomal dominant, OMIM:169500
Early onset or syndromic epilepsy v2.453 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder to Microcephaly 26, primary, autosomal dominant, OMIM:619179
Intellectual disability v3.1401 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder to Microcephaly 26, primary, autosomal dominant, OMIM:619179
Severe microcephaly v2.269 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability; LMNB1-associated developmental disorder to Microcephaly 26, primary, autosomal dominant, OMIM:619179
Fetal anomalies v1.772 LMNB1 Arina Puzriakova Classified gene: LMNB1 as Amber List (moderate evidence)
Fetal anomalies v1.772 LMNB1 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.772 LMNB1 Arina Puzriakova Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.771 LMNB1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: LMNB1.
Fetal anomalies v1.771 GREB1L Arina Puzriakova Phenotypes for gene: GREB1L were changed from Renal hypodysplasia/aplasia 3, 617805; renal agenesis to Renal hypodysplasia/aplasia 3, OMIM:617805; Renal agenesis, MONDO:0018470
Fetal anomalies v1.770 FLNC Arina Puzriakova Tag Q4_21_rating tag was added to gene: FLNC.
Fetal anomalies v1.770 FLNC Arina Puzriakova Classified gene: FLNC as Amber List (moderate evidence)
Fetal anomalies v1.770 FLNC Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.770 FLNC Arina Puzriakova Gene: flnc has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.769 FLNC Arina Puzriakova Publications for gene: FLNC were set to PMID: 33060286; 29858533
Fetal anomalies v1.768 FLNC Arina Puzriakova Phenotypes for gene: FLNC were changed from Arthrogryposis to Arthrogryposis, MONDO:0008779
Mosaic skin disorders - deep sequencing v1.8 GNAQ Eleanor Williams Phenotypes for gene: GNAQ were changed from Phakomatosis pigmentovascularis; Extensive dermal melanocytosis; Sturge Weber syndrome to Phakomatosis pigmentovascularis; Extensive dermal melanocytosis; Sturge-Weber syndrome, somatic, mosaic, OMIM:185300
Mosaic skin disorders - deep sequencing v1.7 GNAQ Eleanor Williams Publications for gene: GNAQ were set to 26778290
Mosaic skin disorders - deep sequencing v1.6 GNAQ Eleanor Williams Mode of pathogenicity for gene: GNAQ 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 v1.5 GNAQ Eleanor Williams reviewed gene: GNAQ: Rating: ; Mode of pathogenicity: None; Publications: 34124757; Phenotypes: Sturge-Weber syndrome, somatic, mosaic, OMIM:185300; Mode of inheritance: None
Fetal anomalies v1.767 EXTL3 Arina Puzriakova Tag Q4_21_rating tag was added to gene: EXTL3.
Fetal anomalies v1.767 EXTL3 Arina Puzriakova Classified gene: EXTL3 as Amber List (moderate evidence)
Fetal anomalies v1.767 EXTL3 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.767 EXTL3 Arina Puzriakova Gene: extl3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.766 EXTL3 Arina Puzriakova Publications for gene: EXTL3 were set to
Intellectual disability v3.1400 EXTL3 Arina Puzriakova Phenotypes for gene: EXTL3 were changed from Immunoskeletal dysplasia with neurodevelopmental abnormalities 617425 to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Skeletal dysplasia v2.146 EXTL3 Arina Puzriakova Phenotypes for gene: EXTL3 were changed from Immunoskeletal dysplasia with neurodevelopmental abnormalities 617425; Immunoskeletal dysplasia with neurodevelopmental abnormalities 617425 to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Primary immunodeficiency or monogenic inflammatory bowel disease v2.484 EXTL3 Arina Puzriakova Phenotypes for gene: EXTL3 were changed from Immunoskeletal dysplasia with neurodevelopmental abnormalities, 617425; EXTL3 deficiency; Platyspondyly, kyphosis, variable skeletal dysplasias, developmental delay; Combined immunodeficiencies with associated or syndromic features to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Fetal anomalies v1.765 EXTL3 Arina Puzriakova Phenotypes for gene: EXTL3 were changed from Immunoskeletal dysplasia with neurodevelopmental abnormalities to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Fetal anomalies v1.764 ENPP1 Arina Puzriakova Classified gene: ENPP1 as Amber List (moderate evidence)
Fetal anomalies v1.764 ENPP1 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.764 ENPP1 Arina Puzriakova Gene: enpp1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.763 ENPP1 Arina Puzriakova Phenotypes for gene: ENPP1 were changed from HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL RECESSIVE, 2; ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1 to Arterial calcification, generalized, of infancy, 1, OMIM:208000
Fetal anomalies v1.762 ENPP1 Arina Puzriakova Publications for gene: ENPP1 were set to
Fetal anomalies v1.761 ENPP1 Arina Puzriakova Tag Q4_21_rating tag was added to gene: ENPP1.
Fetal anomalies v1.761 EIF5A Arina Puzriakova Classified gene: EIF5A as Amber List (moderate evidence)
Fetal anomalies v1.761 EIF5A Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.761 EIF5A Arina Puzriakova Gene: eif5a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1399 EIF5A Arina Puzriakova Phenotypes for gene: EIF5A were changed from Intellectual disability; microcephaly; dysmorphism to Faundes-Banka syndrome, OMIM:619376
Fetal anomalies v1.760 EIF5A Arina Puzriakova Publications for gene: EIF5A were set to PMID: 33547280
Severe microcephaly v2.268 EIF5A Arina Puzriakova Phenotypes for gene: EIF5A were changed from Intellectual disability; microcephaly; dysmorphism to Faundes-Banka syndrome, OMIM:619376
Fetal anomalies v1.759 EIF5A Arina Puzriakova Phenotypes for gene: EIF5A were changed from Faundes-Banka syndrome to Faundes-Banka syndrome, OMIM:619376
Fetal anomalies v1.758 EIF5A Arina Puzriakova Tag Q4_21_rating tag was added to gene: EIF5A.
White matter disorders and cerebral calcification - narrow panel v1.211 CSF1R Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CSF1R.
White matter disorders and cerebral calcification - narrow panel v1.211 CSF1R Arina Puzriakova Publications for gene: CSF1R were set to Parikh et al. Molecular Genetics and Metabolism 114 (2015) 501_605
White matter disorders and cerebral calcification - narrow panel v1.210 CSF1R Arina Puzriakova Added comment: Comment on mode of inheritance: CSF1R is associated with two relevant disorders both including white matter abnormalities and calcifications. One is an adult-onset rapidly progressive neurodegenerative disorder, associated with monoallelic inheritance (Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820). Conversely, biallelic variants cause a condition with a variable onset but mostly childhood (Brain abnormalities, neurodegeneration, and dysosteosclerosis, OMIM:618476).

Both phenotypes are relevant to this panel and therefore the MOI may be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS review.
White matter disorders and cerebral calcification - narrow panel v1.210 CSF1R Arina Puzriakova Mode of inheritance for gene: CSF1R was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Inherited white matter disorders v1.144 CSF1R Arina Puzriakova Publications for gene: CSF1R were set to Parikh et al. Molecular Genetics and Metabolism 114 (2015) 501_605
Inherited white matter disorders v1.143 CSF1R Arina Puzriakova Added comment: Comment on mode of inheritance: MOI was updated from 'Monoallelic' to 'Both mono- and biallelic'. CSF1R is associated with two relevant disorders both including white matter abnormalities - one of which shows biallelic inheritance (Brain abnormalities, neurodegeneration, and dysosteosclerosis, OMIM:618476) while the other is associated with monoallelic inheritance (Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820)
Inherited white matter disorders v1.143 CSF1R Arina Puzriakova Mode of inheritance for gene: CSF1R was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset leukodystrophy v1.32 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from Leukoencephalopathy, diffuse hereditary, with spheroids, 221820 to Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820
White matter disorders and cerebral calcification - narrow panel v1.209 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820; Brain abnormalities, neurodegeneration, and dysosteosclerosis, OMIM:618476
Inherited white matter disorders v1.142 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820; Brain abnormalities, neurodegeneration, and dysosteosclerosis, OMIM:618476
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.49 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from Dementia to Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820; Dementia
Parkinson Disease and Complex Parkinsonism v1.71 CSF1R Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: 'diffuse leukoencephalopathy with spheroids, dementia, motor dysfunction (can include spasticity, ataxia, and parkinsonism) and epilepsy'
Parkinson Disease and Complex Parkinsonism v1.71 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from diffuse leukoencephalopathy with spheroids; dementia, motor dysfunction (can include spasticity, ataxia, and parkinsonism) and epilepsy to Leukoencephalopathy, diffuse hereditary, with spheroids, OMIM:221820
Fetal anomalies v1.758 CSF1R Arina Puzriakova Classified gene: CSF1R as Amber List (moderate evidence)
Fetal anomalies v1.758 CSF1R Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.758 CSF1R Arina Puzriakova Gene: csf1r has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.757 CSF1R Arina Puzriakova Publications for gene: CSF1R were set to PMID: 30982608
Fetal anomalies v1.756 CSF1R Arina Puzriakova Phenotypes for gene: CSF1R were changed from Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) to Brain abnormalities, neurodegeneration, and dysosteosclerosis, OMIM:618476; BANDDOS
Fetal anomalies v1.755 CSF1R Arina Puzriakova Tag Q4_21_rating tag was added to gene: CSF1R.
Fetal anomalies v1.755 CRADD Arina Puzriakova Tag Q4_21_rating tag was added to gene: CRADD.
Fetal anomalies v1.755 CRADD Arina Puzriakova Classified gene: CRADD as Amber List (moderate evidence)
Fetal anomalies v1.755 CRADD Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.755 CRADD Arina Puzriakova Gene: cradd has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.754 CRADD Arina Puzriakova Phenotypes for gene: CRADD were changed from Megalencephaly with Variant Lissencephaly to Mental retardation, autosomal recessive 34, with variant lissencephaly, OMIM:614499
Fetal anomalies v1.753 CRADD Arina Puzriakova Publications for gene: CRADD were set to
Fetal anomalies v1.752 CDK8 Arina Puzriakova Publications for gene: CDK8 were set to PMID: 31742715; 30905399
Fetal anomalies v1.751 CDK8 Arina Puzriakova Phenotypes for gene: CDK8 were changed from Syndromic developmental disorder with hypotonia and behavioural abnormalities to Intellectual developmental disorder with hypotonia and behavioral abnormalities, OMIM:618748
Intellectual disability v3.1398 CDK8 Arina Puzriakova Phenotypes for gene: CDK8 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of cardiovascular system morphology; Hearing impairment; Abnormality of vision; Anorectal anomaly; Seizures; Intellectual developmental disorder with hypotonia and behavioral abnormalities #618748 to Intellectual developmental disorder with hypotonia and behavioral abnormalities, OMIM:618748
Fetal anomalies v1.750 CDK8 Arina Puzriakova Classified gene: CDK8 as Amber List (moderate evidence)
Fetal anomalies v1.750 CDK8 Arina Puzriakova Added comment: Comment on list classification: Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'Q4_21_rating' tag)
Fetal anomalies v1.750 CDK8 Arina Puzriakova Gene: cdk8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.749 CDK8 Arina Puzriakova Tag Q4_21_rating tag was added to gene: CDK8.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.483 RNU7-1 Arina Puzriakova Publications for gene: RNU7-1 were set to 33230297
Gastrointestinal epithelial barrier disorders v1.62 COL7A1 Arina Puzriakova Publications for gene: COL7A1 were set to
Infantile enterocolitis & monogenic inflammatory bowel disease v1.31 COL7A1 Arina Puzriakova Publications for gene: COL7A1 were set to 27537055; 11781296
Primary immunodeficiency or monogenic inflammatory bowel disease v2.482 COL7A1 Arina Puzriakova Publications for gene: COL7A1 were set to 18363753; 23517353; 33346580
Infantile enterocolitis & monogenic inflammatory bowel disease v1.30 RIPK1 Ivone Leong Phenotypes for gene: RIPK1 were changed from Immunodeficiency 57, MIM#618108 to Immunodeficiency 57, OMIM:618108
Infantile enterocolitis & monogenic inflammatory bowel disease v1.29 BACH2 Ivone Leong Classified gene: BACH2 as Green List (high evidence)
Infantile enterocolitis & monogenic inflammatory bowel disease v1.29 BACH2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. This gene is Green on "Primary immunodeficiency" (ID: 298, version 2.481). There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.29 BACH2 Ivone Leong Gene: bach2 has been classified as Green List (High Evidence).
Infantile enterocolitis & monogenic inflammatory bowel disease v1.28 BACH2 Ivone Leong Phenotypes for gene: BACH2 were changed from Immunodeficiency 60, MIM# 618394; inflammatory bowel disease; recurrent sinopulmonary infections to Immunodeficiency 60, OMIM:618394; inflammatory bowel disease; recurrent sinopulmonary infections
Palmoplantar keratodermas v1.9 DSC2 Ivone Leong Tag Q4_21_MOI tag was added to gene: DSC2.
Palmoplantar keratodermas v1.9 DSC2 Ivone Leong reviewed gene: DSC2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratoderma and erythrokeratodermas v1.22 DSC2 Ivone Leong Mode of inheritance for gene: DSC2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratoderma and erythrokeratodermas v1.21 DSC2 Ivone Leong Deleted their review
Ichthyosis and erythrokeratoderma v1.68 DSC2 Ivone Leong Deleted their review
Ichthyosis and erythrokeratoderma v1.68 DSC2 Ivone Leong Deleted their comment
Palmoplantar keratoderma and erythrokeratodermas v1.21 DSC2 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "BIALLELIC, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as Monoallelic variants in this gene also cause disease.
Palmoplantar keratoderma and erythrokeratodermas v1.21 DSC2 Ivone Leong Mode of inheritance for gene: DSC2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1397 ERCC6 Ivone Leong Added comment: Comment on phenotypes: Previous phenotype entry:
Cockayne syndrome, type B, 133540Cerebrooculofacioskeletal syndrome 1, 214150De Sanctis-Cacchione syndrome, 278800{Macular degeneration, age-related, susceptibility to 5}, 613761UV-sensitive syndrome 1, 600630{Lung cancer, susceptibility to}, 211980;DE SANCTIS-CACCHIONE SYNDROME (DSC)
Intellectual disability v3.1397 ERCC6 Ivone Leong Phenotypes for gene: ERCC6 were changed from Cockayne syndrome, type B, 133540Cerebrooculofacioskeletal syndrome 1, 214150De Sanctis-Cacchione syndrome, 278800{Macular degeneration, age-related, susceptibility to 5}, 613761UV-sensitive syndrome 1, 600630{Lung cancer, susceptibility to}, 211980; DE SANCTIS-CACCHIONE SYNDROME (DSC) to De Sanctis-Cacchione syndrome, OMIM:278800
Retinal disorders v2.229 ERCC6 Ivone Leong Phenotypes for gene: ERCC6 were changed from Cockayne syndrome, type B 133540 to Cockayne syndrome, type B, OMIM:133540
Early onset or syndromic epilepsy v2.452 GABRD Helen Lord changed review comment from: Screened the GABRD gene in a cohort of 933 individuals with various childhood-onse epilepsies sequentially referred for diagnostic gene panel testing. The genetic findings were obtained either through targeted epilpesy panels (n=4), WES (n=3) or sanger sequencing (n=3; family 1 patient 6 & 7, family 2 patient 10). Variants classified using the ACMG criteria and badsed on transcript NM_000815.4.
From the original cohort of 933 individuals, presumed pathogenic variants were identified in 3 individuals from 2 unrelated families. Another 7 individuals from 6 families with epilepsy or neurodevelopmental disorders were identified through international collaberations and gene matcher.
The V422I variant occured presumably de novo in two sibs thus one parent must be mosaic.
The T291I variant was detected in an aff mother and her aff twin boys.
The remaining variants M87L, P122A, P257L, L260V & I284T all occured de novo in sporadic patients.
All 7 variants were predicted to be damaging by at least two different prediction tools and had CADD scores above 20. 6 of 7 were absent in gnomAD and our internal dataset. The M87L variant was seen once in gnomAD.
The position of the different variants spans a large part of the delta subunit from the N-terminal end (M87L) to the final transmembrane M4 domain (V442I). Four of the variants (P257L, L260V, I284T & T291I) reside in the M1 and M2 transmembrane domains that are key to forming a functional ion channel. 5 of the 7 variants cause changes to AA residues fully (P122A, P257L & T291I) or highly (L260V & I284T) conserved across human GABAaR subunits.
Functional analysis suggests:
P122A variant results in a 5-fold decrease in the average maximal current amplitude and combined with its increaeed propensity to desensitise - LOF trait.
The 4 variants in the transmembrane domains M1 & M2 (P257L, L260V, I284T, T291I) all resulted in a 3-18 fold increased in current amplitudes - GOF trait.The current amplitude increase in P257L was only 3 fold and this receptor also displayed increased sensitivty to GABA reinforcing the GOF trait.
No functional changes noted for M87L and V422I. As these variants haven't shown any detectable functional changes the 3 individuals carrying these two changes are not included in the phenotypic analysis.

The remaining 7 patients median age of 10 years (ranging from 3-37)/All 6 patients with a GOF variant suffered from generalised epilesy (nost common seizure types atypical absences, generalised myoclonic seizures, tonic seizures and generalised tonic-clonic seizures; occur daily in 4/6 patients and medically refractory in 5/6 patients)and various degrees of learning difficuties or intellectual disability (motor delay in 4/6 with regression or stagnation at seizure onset in at least 2, learning difficulties seen in 6/6 from mild to severe), EEG pattern suggests an underlying cortico-thalmic network tyocial for generalised epilepsys with diffuse spiked and slow waves shown in both humans and animal models~).
The patient with the LOF variant has ASD, normal intelligence and no seizure history.

In summary presumed pathogenic LOF variants were identified in 3 individuals (de novo) and one family (2 twin sibs and mother all aff) with an epilepsy and neurodev disorder.
One GOF variant was identifed (de novo) in a patient with ASD but no seizures.
Two other variants identified in this gene in patients with seizure phenotypes were excluded from phentoypic interpretation as the functional analysis undertaken showed no effect - unclear as to whether these are pathogenic or not.; to: Screened the GABRD gene in a cohort of 933 individuals with various childhood-onset epilepsies sequentially referred for diagnostic gene panel testing. The genetic findings were obtained either through targeted epilpesy panels (n=4), WES (n=3) or sanger sequencing (n=3; family 1 patient 6 & 7, family 2 patient 10). Variants classified using the ACMG criteria and badsed on transcript NM_000815.4.
From the original cohort of 933 individuals, presumed pathogenic variants were identified in 3 individuals from 2 unrelated families. Another 7 individuals from 6 families with epilepsy or neurodevelopmental disorders were identified through international collaberations and gene matcher.
The V422I variant occured presumably de novo in two sibs thus one parent must be mosaic.
The T291I variant was detected in an aff mother and her aff twin boys.
The remaining variants M87L, P122A, P257L, L260V & I284T all occured de novo in sporadic patients.
All 7 variants were predicted to be damaging by at least two different prediction tools and had CADD scores above 20. 6 of 7 were absent in gnomAD and our internal dataset. The M87L variant was seen once in gnomAD.
The position of the different variants spans a large part of the delta subunit from the N-terminal end (M87L) to the final transmembrane M4 domain (V442I). Four of the variants (P257L, L260V, I284T & T291I) reside in the M1 and M2 transmembrane domains that are key to forming a functional ion channel. 5 of the 7 variants cause changes to AA residues fully (P122A, P257L & T291I) or highly (L260V & I284T) conserved across human GABAaR subunits.
Functional analysis suggests:
P122A variant results in a 5-fold decrease in the average maximal current amplitude and combined with its increaesed propensity to desensitise - LOF trait.
The 4 variants in the transmembrane domains M1 & M2 (P257L, L260V, I284T, T291I) all resulted in a 3-18 fold increased in current amplitudes - GOF trait.The current amplitude increase in P257L was only 3 fold and this receptor also displayed increased sensitivty to GABA reinforcing the GOF trait.
No functional changes noted for M87L and V422I. As these variants haven't shown any detectable functional changes the 3 individuals carrying these two changes are not included in the phenotypic analysis.

The remaining 7 patients median age of 10 years (ranging from 3-37)/All 6 patients with a GOF variant suffered from generalised epilesy (nost common seizure types atypical absences, generalised myoclonic seizures, tonic seizures and generalised tonic-clonic seizures; occur daily in 4/6 patients and medically refractory in 5/6 patients)and various degrees of learning difficuties or intellectual disability (motor delay in 4/6 with regression or stagnation at seizure onset in at least 2, learning difficulties seen in 6/6 from mild to severe), EEG pattern suggests an underlying cortico-thalmic network tyocial for generalised epilepsys with diffuse spiked and slow waves shown in both humans and animal models~).
The patient with the LOF variant has ASD, normal intelligence and no seizure history.

In summary presumed pathogenic LOF variants were identified in 3 individuals (de novo) and one family (2 twin sibs and mother all aff) with an epilepsy and neurodev disorder.
One GOF variant was identifed (de novo) in a patient with ASD but no seizures.
Two other variants identified in this gene in patients with seizure phenotypes were excluded from phentoypic interpretation as the functional analysis undertaken showed no effect - unclear as to whether these are pathogenic or not.
Early onset or syndromic epilepsy v2.452 GABRD Helen Lord reviewed gene: GABRD: Rating: GREEN; Mode of pathogenicity: None; Publications: 34633442; Phenotypes: Neurodevelopmental disorders, generalised epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.481 PI4KA Ivone Leong commented on gene: PI4KA: There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.

Review by Sophie Hambleton (Newcastle University):

"The immunological abnormalities in PI4KA def are obviously rather variable and a slight side-show to the primary GI and neurologic pathology – however that is a detail that should come out when any putative case is reviewed in detail so I would include this as a “CID with associated or syndromic features” on the same basis as TTC7A"
Primary immunodeficiency or monogenic inflammatory bowel disease v2.481 PI4KA Ivone Leong Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.243
Primary immunodeficiency or monogenic inflammatory bowel disease v2.481 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to Primary immunodeficiency. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
DDG2P v2.50 ATG7 Dmitrijs Rots gene: ATG7 was added
gene: ATG7 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG7 were set to PMID:34161705
Phenotypes for gene: ATG7 were set to developmental delay; ataxia
Review for gene: ATG7 was set to GREEN
Added comment: Zornitsa Stark wrote for this gene in Ataxia panel:
"12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The more severely affected individuals had spastic paraplegia and inability to walk.

Functional data including mouse model. "

Should be also on ID panel.
Sources: Literature
DDG2P v2.50 RAP1GDS1 Dmitrijs Rots gene: RAP1GDS1 was added
gene: RAP1GDS1 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: RAP1GDS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAP1GDS1 were set to PMID: 33875846
Phenotypes for gene: RAP1GDS1 were set to Intellectual disability, developmental delay
Review for gene: RAP1GDS1 was set to GREEN
Added comment: Additional cases (three with same splice variant, which segregates in one family) and one frameshift variant reported in PMID: 33875846. Cases seem to overlap ones reported in PMID: 32431071.
Sources: Literature
Intellectual disability v3.1396 RAP1GDS1 Dmitrijs Rots changed review comment from: Additional cases (three with same splice variant, which segregates in one family) and one frameshift variant reported in PMID: 33875846; to: Additional cases (three with same splice variant, which segregates in one family) and one frameshift variant reported in PMID: 33875846. Cases seem to overlap those reported in PMID: 32431071.
Intellectual disability v3.1396 RAP1GDS1 Dmitrijs Rots reviewed gene: RAP1GDS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846; Phenotypes: Intellectual disability, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1396 PLK1 Dmitrijs Rots gene: PLK1 was added
gene: PLK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK1 were set to PMID: 33875846
Phenotypes for gene: PLK1 were set to Epilepsy; microcephaly; intellectual disability
Review for gene: PLK1 was set to GREEN
Added comment: >5 cases with epileptic encephalopathy with homozygous variants in PMID: 33875846
Sources: Literature
Early onset or syndromic epilepsy v2.452 PLK1 Dmitrijs Rots gene: PLK1 was added
gene: PLK1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PLK1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PLK1 were set to Epilepsy; microcephaly; intellectual disability
Review for gene: PLK1 was set to GREEN
Added comment: >5 cases with epileptic encephalopathy with homozygous variants in PMID: 33875846
Sources: Literature
Intellectual disability v3.1396 RAB11A Dmitrijs Rots reviewed gene: RAB11A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846, 26902202; Phenotypes: microcephaly, brain anomalies, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v2.50 RAB11A Dmitrijs Rots reviewed gene: RAB11A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846, 26902202; Phenotypes: microcephaly, brain anomalies, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.749 RAB11A Dmitrijs Rots reviewed gene: RAB11A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846, 26902202; Phenotypes: microcephaly, brain anomalies, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v2.50 TAF4 Dmitrijs Rots gene: TAF4 was added
gene: TAF4 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: TAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAF4 were set to 33875846
Phenotypes for gene: TAF4 were set to Developmental delay
Penetrance for gene: TAF4 were set to unknown
Review for gene: TAF4 was set to GREEN
Added comment: From the literature:
"A heterozygous de novo variant (frameshift) was reported in TAF4 by Kosmicki et al., in a patient with autism.36 The gene has no phenotypic association in OMIM (accessed 12 October 2020). Within this study, we identified two additional de novo LoF variants (splicing and nonsense) in two unrelated patients with dysmorphic features and NDD. TAF4 is highly intolerant to LoF as documented in gnomAD (pLi = 1). Expression of TAF4 varies during development and in the processes of cell differentiation; TAF4 is detected in various regions of the human brain, and it is believed to control the differentiation of human neural progenitor cells having a role in the regulation of neural development and brain function.37 The current data suggests that TAF4 haploinsufficiency leads to NDD in humans."
Sources: Literature
IUGR and IGF abnormalities v1.41 PAPPA2 Dmitrijs Rots reviewed gene: PAPPA2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846, 26902202; Phenotypes: Short stature, dysmorphism, mild microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 MMP15 Dmitrijs Rots gene: MMP15 was added
gene: MMP15 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MMP15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMP15 were set to PMID: 33875846
Phenotypes for gene: MMP15 were set to Cholestasis; congenital heart disease
Review for gene: MMP15 was set to AMBER
Added comment: Three cases from two families with biallelic variants and very similar phenotype including rare combination of symtoms (allagile-like) cholestasis with hepatomegaly and congenital heart disease. Phenotype could be important for fetal panel.
Sources: Literature
Cholestasis v1.88 MMP15 Dmitrijs Rots gene: MMP15 was added
gene: MMP15 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: MMP15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMP15 were set to PMID: 33875846
Phenotypes for gene: MMP15 were set to Cholestasis; congenital heart disease
Penetrance for gene: MMP15 were set to unknown
Review for gene: MMP15 was set to GREEN
Added comment: Three cases from two families with biallelic variants and very similar phenotype including rare combination of symtoms (allagile-like) cholestasis and congenital heart disease.
Sources: Literature
Fetal anomalies v1.749 PRRX1 Rhiannon Mellis gene: PRRX1 was added
gene: PRRX1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PRRX1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PRRX1 were set to 21294718; 22211708; 22674740; 23444262
Phenotypes for gene: PRRX1 were set to Agnathia-otocephaly complex
Review for gene: PRRX1 was set to GREEN
Added comment: At least 4 unrelated cases reported with agnathia-otocephaly complex
Sources: Literature
Fetal anomalies v1.749 POLR1B Rhiannon Mellis gene: POLR1B was added
gene: POLR1B was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: POLR1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR1B were set to PMID: 31649276
Phenotypes for gene: POLR1B were set to Treacher-Collins syndrome 4
Review for gene: POLR1B was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already flagged for upgrade to Green on the following other PanelApp panel(s): Clefting, Skeletal dysplasias

Details of review:
PMID: 31649276 - Sanchez et al 2020 - using exome sequencing identified 6 patients (5 unrelated families) with Treacher Collins syndrome with heterozygous missense variants in POLR1B.
Sources: Expert Review, Literature
Fetal anomalies v1.749 CSF1R Rhiannon Mellis gene: CSF1R was added
gene: CSF1R was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: CSF1R was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSF1R were set to PMID: 30982608
Phenotypes for gene: CSF1R were set to Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS)
Review for gene: CSF1R was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Details of review:
Homozygous variants cause Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). Skeletal phenotype is osteopetrosis, dysosteosclerosis, platyspondyly, widened metaphyses. Brain anomalies include ACC and Dandy walker. At least one reported case of prenatal presentation with multiple brain anomalies - PubMed: 30982608

NB Bilallelic LOF variants cause this condition with fetally relevant phenotype but Monoallelic variants with dominant-negative effect cause an adult-onset neurodegenerative disease. Only for fetal reporting in BIALLELIC form
Sources: Expert Review
Fetal anomalies v1.749 LMNB2 Rhiannon Mellis gene: LMNB2 was added
gene: LMNB2 was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNB2 were set to PMID: 33033404
Phenotypes for gene: LMNB2 were set to Microcephaly 27, primary, autosomal dominant
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Severe microcephaly (pending)

Details of review:
Parry et al 2020 (PMID: 33033404) report on a cohort from DDD and 100k genomes studies: 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6) - phenotype of severe congenital microcephaly and ID (otherwise non-syndromic).
Sources: Expert Review, Literature
Fetal anomalies v1.749 LMNB1 Rhiannon Mellis gene: LMNB1 was added
gene: LMNB1 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNB1 were set to PMID: 33033404
Phenotypes for gene: LMNB1 were set to Microcephaly 26, primary, autosomal dominant
Review for gene: LMNB1 was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Severe microcephaly (pending)

Details of review:
Parry et al 2020 (PMID: 33033404) report on a cohort from DDD and 100k genomes studies: 13 individuals with heterozygous variant in LMNB1 (N=7) and LMNB2 (N=6) - phenotype of severe congenital microcephaly and ID (otherwise non-syndromic).
Sources: Literature, Expert Review
Fetal anomalies v1.749 EIF5A Rhiannon Mellis gene: EIF5A was added
gene: EIF5A was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF5A were set to PMID: 33547280
Phenotypes for gene: EIF5A were set to Faundes-Banka syndrome
Review for gene: EIF5A was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Details of review:
Faundes et al 2021 (PMID: 33547280) report this as a novel disease gene associated with micrognathia, microcephaly, IUGR and Kabuki-like phenotype. Now on OMIM as of August 2021. 7 unrelated patients in this publication.
Sources: Literature, Expert Review
Fetal anomalies v1.749 PRIM1 Rhiannon Mellis gene: PRIM1 was added
gene: PRIM1 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIM1 were set to PMID: 33060134
Phenotypes for gene: PRIM1 were set to Primordial dwarfism
Review for gene: PRIM1 was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Details of review:
Parry et al 2020 (PMID: 33060134) report this as a novel disease gene - biallelic LOF mutations in 5 patients (from 4 families) with primordial dwarfism phenotype, including prenatal features of IUGR and extreme microcephaly with simplified gyri.
Sources: Literature, Expert Review
Fetal anomalies v1.749 MN1 Rhiannon Mellis commented on gene: MN1: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Agreed that the phenotype is fetally relevant (structural brain abnormalities e.g. polymicrogyria, cerebellar hypoplasia, craniofacial features etc.) support adding to the Fetal anomalies panel as a Green gene.
Fetal anomalies v1.749 EXTL3 Rhiannon Mellis gene: EXTL3 was added
gene: EXTL3 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: EXTL3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: EXTL3 were set to Immunoskeletal dysplasia with neurodevelopmental abnormalities
Review for gene: EXTL3 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott.

Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): Skeletal dysplasia
Sources: Expert Review
Fetal anomalies v1.749 GREB1L Rhiannon Mellis commented on gene: GREB1L: This gene and phenotype were re-reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene as per previous reviews (unclear on reason for change from Green to Amber previously)
Fetal anomalies v1.749 EXOC3L2 Rhiannon Mellis reviewed gene: EXOC3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30327448, 28749478, 27894351; Phenotypes: Dandy Walker malformation, Meckel-Gruber like phenotype; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 FLNC Rhiannon Mellis changed review comment from: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Distal myopathies

Details of review:
In this paper by Ravenscroft et al 2020, the proband presented at birth with hip dislocation, clenched hands, adducted thumbs, small mouth and high palate and posteriorly rotated ears. On examination, she had mild arthrogryposis, reduced shoulder movement, elbow dimples and scoliosis. Kiselev et al (PMID: 29858533) also described a series of four cases with early onset restrictive cardiomyopathy (RCM) and congenital myopathy. Two of these also presented with arthrogryposis at birth.
Sources: Literature, Expert Review; to: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Distal myopathies; Neuromuscular disorders; flagged for upgrade to Green on Arthrogryposis panel

Details of review:
In this paper by Ravenscroft et al 2020, the proband presented at birth with hip dislocation, clenched hands, adducted thumbs, small mouth and high palate and posteriorly rotated ears. On examination, she had mild arthrogryposis, reduced shoulder movement, elbow dimples and scoliosis. Kiselev et al (PMID: 29858533) also described a series of four cases with early onset restrictive cardiomyopathy (RCM) and congenital myopathy. Two of these also presented with arthrogryposis at birth.
Sources: Literature, Expert Review
Fetal anomalies v1.749 FLNC Rhiannon Mellis gene: FLNC was added
gene: FLNC was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: FLNC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FLNC were set to PMID: 33060286; 29858533
Phenotypes for gene: FLNC were set to Arthrogryposis
Review for gene: FLNC was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Distal myopathies

Details of review:
In this paper by Ravenscroft et al 2020, the proband presented at birth with hip dislocation, clenched hands, adducted thumbs, small mouth and high palate and posteriorly rotated ears. On examination, she had mild arthrogryposis, reduced shoulder movement, elbow dimples and scoliosis. Kiselev et al (PMID: 29858533) also described a series of four cases with early onset restrictive cardiomyopathy (RCM) and congenital myopathy. Two of these also presented with arthrogryposis at birth.
Sources: Literature, Expert Review
Fetal anomalies v1.749 SMARCE1 Rhiannon Mellis reviewed gene: SMARCE1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32732226, 32436246, 32410215; Phenotypes: Coffin Siris syndrome 5; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.749 SMARCC1 Rhiannon Mellis reviewed gene: SMARCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32732226; Phenotypes: Congenital hydrocephalus, Aqueduct stenosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arthrogryposis v3.137 SLC6A9 Rhiannon Mellis reviewed gene: SLC6A9: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31875334, 27773429, 32712301, 33269555; Phenotypes: Arthrogryposis multiplex congenita, Glycine encephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 SLC6A9 Rhiannon Mellis reviewed gene: SLC6A9: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31875334, 27773429, 32712301, 33269555; Phenotypes: Glycine encephalopathy with Arthrogryposis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 CRADD Rhiannon Mellis reviewed gene: CRADD: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29947050, 27773430; Phenotypes: Mental retardation, autosomal recessive 34, with variant lissencephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 CDK8 Rhiannon Mellis gene: CDK8 was added
gene: CDK8 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: CDK8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDK8 were set to PMID: 31742715; 30905399
Phenotypes for gene: CDK8 were set to Syndromic developmental disorder with hypotonia and behavioural abnormalities
Review for gene: CDK8 was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Intellectual disability; Severe paediatric disorders

Details of review:
Aggarwal et al 2020 report a heterozygous nonsense variant in a fetus with ventriculomegaly and Ebstein anomaly resulting in IUFD. Post-mortem found additionally congenital diaphragmatic hernia, common atrium and facial dysmorphism. This nonsense variant is at the same position as a hotspot for missense variants reported in a paediatric cohort (Calpena et al 2019, PMID: 30905399) with overlapping but milder phenotype: half of the 12 children in that cohort had cardiac defects, most had dysmorphic features - hence Aggarwal et al propose that this is a more severe (prenatal) presentation of the same multiple malformation syndrome, caused here by a nonsense rather than missense mutation.
Sources: Literature, Expert Review
Fetal anomalies v1.749 ENPP1 Rhiannon Mellis reviewed gene: ENPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31742715, 19521093, 19813208; Phenotypes: Generalised arterial calcification of infancy (GACI); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.452 SNIP1 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: SNIP1.
Early onset or syndromic epilepsy v2.452 SNIP1 Sarah Leigh commented on gene: SNIP1: Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, to decide whether this gene could be green, as the disease association has only been associated with a the founder variant.
Intellectual disability v3.1396 SNIP1 Sarah Leigh commented on gene: SNIP1: Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, to decide whether this gene could be green, as the disease association has only been associated with a the founder variant.
Intellectual disability v3.1396 SNIP1 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: SNIP1.
CAKUT v1.165 TMEM260 Sarah Leigh edited their review of gene: TMEM260: Changed rating: AMBER
CAKUT v1.165 TMEM260 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least eight variants have been reported in at least six unrelated cases. The variants included: one multi-exon deletion resulting in a frameshift, two smaller frameshifting deletions, two nonsense, one splicing change and two missense changes, one of which was shown by cDNA sequencing to result in skipping of exon 3 (PMID 34612517).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least eight variants have been reported in at least six unrelated cases. The variants included: one multi-exon deletion resulting in a frameshift, two smaller frameshifting deletions, two nonsense, one splicing change and two missense changes, one of which was shown by cDNA sequencing to result in skipping of exon 3 (PMID 34612517). Renal features were seen in patients as follows: elevated creatinine levels (6/12), horse-shoe kidneys (1/12) and renal cysts (1/12)(PMID 34612517).
Ataxia and cerebellar anomalies - narrow panel v2.243 DHDDS Arina Puzriakova Classified gene: DHDDS as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.243 DHDDS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Ataxia and cerebellar anomalies - narrow panel v2.243 DHDDS Arina Puzriakova Gene: dhdds has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.242 DHDDS Arina Puzriakova gene: DHDDS was added
gene: DHDDS was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q4_21_rating tags were added to gene: DHDDS.
Mode of inheritance for gene: DHDDS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DHDDS were set to 29100083; 33798445; 34182312; 34382076
Phenotypes for gene: DHDDS were set to Developmental delay and seizures with or without movement abnormalities, OMIM:617836
Review for gene: DHDDS was set to GREEN
Added comment: Monoallelic variants are associated with a neurodevelopmental disorder comprising infantile or childhood-onset DD/ID, epilepsy and a variable movement phenotype which typically initially manifests as action myoclonus/cortical tremor and in some cases ataxia - at least 11 unrelated cases of ataxia reported in literature.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v1.166 DHDDS Arina Puzriakova Classified gene: DHDDS as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.166 DHDDS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Childhood onset dystonia, chorea or related movement disorder v1.166 DHDDS Arina Puzriakova Gene: dhdds has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.165 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from to Developmental delay and seizures with or without movement abnormalities, OMIM:617836
Childhood onset dystonia, chorea or related movement disorder v1.164 DHDDS Arina Puzriakova Publications for gene: DHDDS were set to
Childhood onset dystonia, chorea or related movement disorder v1.163 DHDDS Arina Puzriakova Mode of inheritance for gene: DHDDS was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset dystonia, chorea or related movement disorder v1.162 DHDDS Arina Puzriakova Tag Q4_21_rating tag was added to gene: DHDDS.
Childhood onset dystonia, chorea or related movement disorder v1.162 DHDDS Arina Puzriakova reviewed gene: DHDDS: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100083, 32654954, 33798445, 34182312, 34382076, 34504728; Phenotypes: Developmental delay and seizures with or without movement abnormalities, OMIM:617836; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Long QT syndrome v2.28 ALG10 Sarah Leigh Mode of inheritance for gene: ALG10 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Long QT syndrome v2.27 ALG10 Sarah Leigh Publications for gene: ALG10 were set to 15280551
Long QT syndrome v2.26 ALG10 Sarah Leigh reviewed gene: ALG10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Long QT syndrome v2.26 ALG10 Sarah Leigh Phenotypes for gene: ALG10 were changed from {Acquired long QT syndrome, reduced susceptibility to}, 613688 to Progressive myoclonus epilepsy; CDG
Long QT syndrome v2.25 ALG10 Sarah Leigh Tag new-gene-name was removed from gene: ALG10.
Short QT syndrome v2.9 Sarah Leigh removed gene:ALG10 from the panel
Short QT syndrome v2.8 ALG10B Sarah Leigh Entity copied from Cardiac arrhythmias - previous panel v1.5
Short QT syndrome v2.8 ALG10B Sarah Leigh gene: ALG10B was added
gene: ALG10B was added to Short QT syndrome. Sources: Other
Mode of inheritance for gene: ALG10B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ALG10B were set to 15280551
Phenotypes for gene: ALG10B were set to {Acquired long QT syndrome, reduced susceptibility to} OMIM:613688
Long QT syndrome v2.25 ALG10B Sarah Leigh Entity copied from Cardiac arrhythmias - previous panel v1.5
Long QT syndrome v2.25 ALG10B Sarah Leigh gene: ALG10B was added
gene: ALG10B was added to Long QT syndrome. Sources: Other
Mode of inheritance for gene: ALG10B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ALG10B were set to 15280551
Phenotypes for gene: ALG10B were set to {Acquired long QT syndrome, reduced susceptibility to} OMIM:613688
Intellectual disability v3.1396 DHDDS Arina Puzriakova Publications for gene: DHDDS were set to 29100083; 27343064
Early onset or syndromic epilepsy v2.452 DHDDS Arina Puzriakova Publications for gene: DHDDS were set to 27343064; 29100083
Intellectual disability v3.1395 DHDDS Arina Puzriakova Tag Q4_21_MOI tag was added to gene: DHDDS.
Intellectual disability v3.1395 DHDDS Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Both mono- and biallelic' to 'Monoallelic' at the next GMS panel update. Monoallelic variants are associated with a neurodevelopmental disorder comprising DD/ID, epilepsy and a variable movement disorder phenotype - >3 unrelated individuals reported in literature. To date, only one individual with biallelic variants and ID has been reported (PMID: 27343064). This patient presented with glycosylation defects but no corroborating cases have been reported since.
As only one patient has been described with biallelic inheritance and this phenotype, MOI should be set to 'Monoallelic' until evidence of additional cases emerges - biallelic variants would still be picked up by the Genomics England pipeline under this MOI.
Intellectual disability v3.1395 DHDDS Arina Puzriakova Mode of inheritance for gene: DHDDS was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.451 DHDDS Arina Puzriakova Tag Q4_21_MOI tag was added to gene: DHDDS.
Early onset or syndromic epilepsy v2.451 DHDDS Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Both mono- and biallelic' to 'Monoallelic' at the next GMS panel update. Monoallelic variants are associated with a neurodevelopmental disorder comprising DD/ID, epilepsy and a variable movement disorder phenotype - >3 unrelated individuals reported in literature. To date, only one individual with biallelic variants and epilepsy has been reported (PMID: 27343064). This patient presented with glycosylation defects but no corroborating cases have been reported since.
As only one patient has been described with biallelic inheritance and this phenotype, MOI should be set to 'Monoallelic' until evidence of additional cases emerges - biallelic variants would still be picked up by the Genomics England pipeline under this MOI.
Early onset or syndromic epilepsy v2.451 DHDDS Arina Puzriakova Mode of inheritance for gene: DHDDS was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.190 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861; Posterior segment abnormalities to Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861
Undiagnosed metabolic disorders v1.488 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861; Posterior segment abnormalities to Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861
Intellectual disability v3.1394 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Developmental delay and seizures with or without movement abnormalities, 617836; ?Congenital disorder of glycosylation, type 1bb, 613861 to Developmental delay and seizures with or without movement abnormalities, OMIM:617836
Early onset or syndromic epilepsy v2.450 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Developmental delay and seizures with or without movement abnormalities, 617836; developmental and epileptic encephalopathy (DEE); ?Congenital disorder of glycosylation, type 1bb,613861 to Developmental delay and seizures with or without movement abnormalities, OMIM:617836
CAKUT v1.165 TMEM260 Sarah Leigh Deleted their comment
CAKUT v1.165 TMEM260 Sarah Leigh Entity copied from Fetal anomalies v1.749
CAKUT v1.165 TMEM260 Sarah Leigh gene: TMEM260 was added
gene: TMEM260 was added to CAKUT. Sources: Expert Review Amber,PAGE DD-Gene2Phenotype
Q4_21_rating tags were added to gene: TMEM260.
Mode of inheritance for gene: TMEM260 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM260 were set to 28318500; 34612517
Phenotypes for gene: TMEM260 were set to Structural heart defects and renal anomalies syndrome, OMIM:617478; Structural heart defects and renal anomalies syndrome, MONDO:0044321
Likely inborn error of metabolism v2.189 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa 59 613861; ?Congenital disorder of glycosylation, type 1bb 613861 to Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861; Posterior segment abnormalities
Undiagnosed metabolic disorders v1.487 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa (other congenital disorders of glycosylation); Posterior segment abnormalities to Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861; Posterior segment abnormalities
Congenital disorders of glycosylation v2.78 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa 59 613861; ?Congenital disorder of glycosylation, type 1bb 613861 to Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861
Glaucoma (developmental) v1.41 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Eye Disorders to Retinitis pigmentosa 59, OMIM:613861
Glaucoma (developmental) v1.40 DHDDS Arina Puzriakova Mode of inheritance for gene: DHDDS was changed from to BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.88 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa 59, 613861; Eye Disorders to Retinitis pigmentosa 59, OMIM:613861
Retinal disorders v2.228 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Eye Disorders; Retinitis pigmentosa; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa 59, 613861 to Retinitis pigmentosa 59, OMIM:613861
Rhabdomyolysis and metabolic muscle disorders v1.57 FKTN Sarah Leigh commented on gene: FKTN: Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, in response to Zornitza Stark's Red review, that Rhabdomyolysis is not a significant feature of this muscle disorder.
Rhabdomyolysis and metabolic muscle disorders v1.57 FKTN Sarah Leigh Tag Q4_21_expert_review tag was added to gene: FKTN.
Adult onset neurodegenerative disorder v2.201 FIG4 Sarah Leigh changed review comment from: In with respect to Ian Berry's proposed demotion of FIG4, after reviewing PMID:19118816. Helen Brittain (Genomics England Clinical Fellow) has suggested the rating of this gene should be considered by TEWG oversight committee, as there is a lack of evidence for ALS.; to: Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, in response to Ian Berry's proposed demotion of FIG4, after reviewing PMID:19118816, which shows a lack of evidence for ALS.
Adult onset neurodegenerative disorder v2.201 FIG4 Sarah Leigh edited their review of gene: FIG4: Added comment: In with respect to Ian Berry's proposed demotion of FIG4, after reviewing PMID:19118816. Helen Brittain (Genomics England Clinical Fellow) has suggested the rating of this gene should be considered by TEWG oversight committee, as there is a lack of evidence for ALS.; Changed rating: AMBER
Adult onset neurodegenerative disorder v2.201 FIG4 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: FIG4.
Short QT syndrome v2.7 ALG10 Sarah Leigh changed review comment from: Not associated with Short QT phenotype in OMIM or in Gen2Phen.; to: ALG10 OMIM:618355 is not associated with Short QT phenotype in OMIM or in Gen2Phen. However, ALG10B OMIM:603313 is associated with Long QT syndrome, acquired, reduced susceptibility to OMIM:613688 (PMID:15280551).
Long QT syndrome v2.24 ALG10 Sarah Leigh Publications for gene: ALG10 were set to
Short QT syndrome v2.7 ALG10 Sarah Leigh commented on gene: ALG10: The correct gene name is: ALG10B OMIM:603313
Fetal anomalies v1.749 ACAN Zornitza Stark reviewed gene: ACAN: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepimetaphyseal dysplasia, aggrecan type, MIM# 612813; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.749 CYP19A1 Arina Puzriakova Phenotypes for gene: CYP19A1 were changed from Aromatase deficiency 613546; Aromatase excess syndrome 139300 to Aromatase deficiency, OMIM:613546; Aromatase excess syndrome, OMIM:139300
Fetal anomalies v1.748 CYP19A1 Arina Puzriakova Mode of inheritance for gene: CYP19A1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.747 CYP19A1 Arina Puzriakova Mode of inheritance for gene: CYP19A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Primary ovarian insufficiency v1.52 CYP19A1 Arina Puzriakova Phenotypes for gene: CYP19A1 were changed from Aromatase deficiency 613546 to Aromatase deficiency, OMIM:613546
Differences in sex development v2.51 CYP19A1 Arina Puzriakova Phenotypes for gene: CYP19A1 were changed from Gender Assignment Gene Panel (UKGTN); Endocrine disorders including disorders of sexual development; Aromatase deficiency, 613546 to Aromatase deficiency, OMIM:613546
Differences in sex development v2.50 CYP11A1 Arina Puzriakova Phenotypes for gene: CYP11A1 were changed from Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN); Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, 613743 to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM:613743
Congenital adrenal hypoplasia v2.7 CYP11A1 Arina Puzriakova Phenotypes for gene: CYP11A1 were changed from Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, 613743; Congenital Adrenal Insufficiency to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM:613743
Fetal anomalies v1.746 CYP11A1 Arina Puzriakova Phenotypes for gene: CYP11A1 were changed from Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete 613743 to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM:613743
Fetal anomalies v1.745 CRYBB3 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS panel update. CRYBB3 is associated with congenital cataract (MIM# 609741) which can have monoallelic or biallelic inheritance. Both MOIs for this phenotype are listed in OMIM and G2P.
Fetal anomalies v1.745 CRYBB3 Arina Puzriakova Mode of inheritance for gene: CRYBB3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.744 CRYBB3 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CRYBB3.
Fetal anomalies v1.744 CRYBB3 Arina Puzriakova Phenotypes for gene: CRYBB3 were changed from CATARACT, CONGENITAL NUCLEAR, AUTOSOMAL RECESSIVE 2 to Cataract 22, OMIM:609741
Intellectual disability v3.1393 CRYBB3 Arina Puzriakova Phenotypes for gene: CRYBB3 were changed from Cataract 22, autosomal recessive, 609741 to Cataract 22, OMIM:609741
Structural eye disease v1.87 CRYBB3 Arina Puzriakova Phenotypes for gene: CRYBB3 were changed from Cataract 22, autosomal recessive, 609741 to Cataract 22, OMIM:609741
Intellectual disability v3.1392 CRYBB3 Arina Puzriakova Mode of inheritance for gene: CRYBB3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.88 CRYBB3 Arina Puzriakova Phenotypes for gene: CRYBB3 were changed from Congenital Nuclear Cataract; Cataract 22, autosomal recessive, 609741 to Cataract 22, OMIM:609741
Structural eye disease v1.86 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from CATARACT 16, MULTIPLE TYPES, 613763 to Cataract 16, multiple types, OMIM:613763
Congenital myopathy v2.64 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:61386 to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:613869
Arthrogryposis v3.137 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:61386 to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:613869
Paediatric or syndromic cardiomyopathy v1.59 CRYAB Arina Puzriakova Mode of inheritance for gene: CRYAB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric or syndromic cardiomyopathy v1.58 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, fatal infantile hypertrophy, alpha B crystallin related, 613869; Cardiomyopathy, dilated, 1II, to Cardiomyopathy, dilated, 1II, OMIM:615184; Myopathy, myofibrillar, 2, OMIM:608810
Dilated and arrhythmogenic cardiomyopathy v1.26 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from to Cardiomyopathy, dilated, 1II, OMIM:615184; Myopathy, myofibrillar, 2, OMIM:608810
Congenital myopathy v2.63 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, 2 608810; Myopathy, myofibrillar, fatal infantile hypertrophy, alpha-B crystallin-related 613869 to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:61386
Arthrogryposis v3.136 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, 2, 608810Cataract 16, multiple types, 613763Myopathy, myofibrillar, fatal infantile hypertrophy, alpha-B crystallin-related, 613869Cardiomyopathy, dilated, 1II, 615184; Myofibrillar Myopathy, Dominant to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:61386
Dilated Cardiomyopathy and conduction defects v1.72 CRYAB Arina Puzriakova Mode of inheritance for gene: CRYAB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.71 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Cardiomyopathy, dilated, 1II, to Cardiomyopathy, dilated, 1II, OMIM:615184; Myopathy, myofibrillar, 2, OMIM:608810
Hypertrophic cardiomyopathy v2.31 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from "Myopathy, myofibrillar, fatal infantile hypertrophy, alpha ‐ B crystallin ‐ related, 613869" to Myopathy, myofibrillar, 2, OMIM:608810
Distal myopathies v1.33 CRYAB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CRYAB.
Distal myopathies v1.33 CRYAB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS panel update. Predominantly monoallelic inheritance, though there are rare cases with biallelic variants where individuals tend to be more severely affected.
Distal myopathies v1.33 CRYAB Arina Puzriakova Mode of inheritance for gene: CRYAB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Distal myopathies v1.32 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar 2, 608810 to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:613869
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.32 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Cataract 16, multiple types, 613763; myofibrillar myopathy to Myopathy, myofibrillar, 2, OMIM:608810; Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related, OMIM:613869
Rare multisystem ciliopathy disorders v1.149 EVC Ivone Leong Added comment: Comment on phenotypes: It is also associated with ?Weyers acrofacial dysostosis, OMIM:193530.
Rare multisystem ciliopathy disorders v1.149 EVC Ivone Leong Phenotypes for gene: EVC were changed from Ellis-van Creveld syndrome, 225500; Weyers acrodental dysostosis, 193530 to Ellis-van Creveld syndrome, OMIM:225500
Neurological ciliopathies v1.21 EVC Ivone Leong Added comment: Comment on phenotypes: It is also associated with ?Weyers acrofacial dysostosis, OMIM:193530.
Neurological ciliopathies v1.21 EVC Ivone Leong Phenotypes for gene: EVC were changed from Ellis-van Creveld syndrome, 225500; Weyers acrodental dysostosis, 193530 to Ellis-van Creveld syndrome, OMIM:225500
Skeletal ciliopathies v1.11 EVC Ivone Leong Added comment: Comment on phenotypes: It is also associated with ?Weyers acrofacial dysostosis, OMIM:193530.
Skeletal ciliopathies v1.11 EVC Ivone Leong Phenotypes for gene: EVC were changed from Ellis-van Creveld syndrome, 225500; Weyers acrodental dysostosis, 193530 to Ellis-van Creveld syndrome, OMIM:225500
DDG2P v2.50 CRYBB1 Ivone Leong Tag Q4_21_MOI tag was added to gene: CRYBB1.
DDG2P v2.50 CRYBB1 Ivone Leong reviewed gene: CRYBB1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 COL7A1 Sophie Hambleton reviewed gene: COL7A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32084423; Phenotypes: epidermolysis bullosa, bloody diarrhoea; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 RNU7-1 Sophie Hambleton reviewed gene: RNU7-1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.87 CRYAB Arina Puzriakova Phenotypes for gene: CRYAB were changed from Myopathy, myofibrillar, 2, 608810; Posterior Polar Cataract to Cataract 16, multiple types, OMIM:613763; Myopathy, myofibrillar, 2, OMIM:608810
Intellectual disability v3.1391 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from Epiphyseal dysplasia, multiple, 3, 600969; Epiphyseal dysplasia, multiple, with myopathy; {Intervertebral disc disease, susceptibility to}, 603932 to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Monogenic hearing loss v2.206 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from Stickler syndrome to Stickler syndrome, MONDO:0019354
Fetal anomalies v1.743 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from MULTIPLE EPIPHYSEAL DYSPLASIA TYPE 3 to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Skeletal dysplasia v2.145 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from MED; multiple epiphyseal dysplasia; Epiphyseal dysplasia, multiple, with myopathy; Stickler syndrome type VI; multiple epiphyseal dysplasia 3, with or without myopathy - 600969; Multiple Epiphyseal Dysplasia, Dominant; Mutiple Epiphyseal Dysplasia to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Congenital myopathy v2.62 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from Epiphyseal dysplasia, multiple, 3, with or without myopathy 600969 to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Arthrogryposis v3.135 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from Epiphyseal dysplasia, multiple, 3, 600969Epiphyseal dysplasia, multiple, with myopathy{Intervertebral disc disease, susceptibility to}, 603932 to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Arthrogryposis v3.134 COL9A3 Arina Puzriakova Mode of inheritance for gene: COL9A3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Multiple Epiphyseal Dysplasia v1.6 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from multiple epiphyseal dysplasia; Multiple Epiphyseal Dysplasia, Dominant; Epiphyseal dysplasia, multiple, with myopathy to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Multiple Epiphyseal Dysplasia v1.5 COL9A3 Arina Puzriakova Publications for gene: COL9A3 were set to PMID: 21922596; 20301302; 20301479
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 CARS Michael Yau gene: CARS was added
gene: CARS was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Expert list
Mode of inheritance for gene: CARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CARS were set to PMID 30824121
Phenotypes for gene: CARS were set to Microcephaly; Developmental Delay; Brittle Hair
Penetrance for gene: CARS were set to Complete
Review for gene: CARS was set to GREEN
Added comment: Name: cysteinyl-tRNA synthetase 1; Symbol: CARS1 ; HGNC ID: 1493

Current Status: Not in R227 Panel. This gene was added to the DDG2P panel in March 2019 as a amber gene and the reviewer noted the following: "Microcephaly Developmental Delay and Brittle Hair and Nails. DDG2P Disease confidence: probable. DDG2P mode of pathogenicity/mutation consequence: loss of function. DDG2P mode of inheritance: biallelic." Proposed change: GREEN

The CARS1 genes was added to the DDG2P panel in March 2019 as an amber gene and the reviewer noted the following: "Microcephaly Developmental Delay and Brittle Hair and Nails. DDG2P Disease confidence: probable. DDG2P mode of pathogenicity/mutation consequence: loss of function. DDG2P mode of inheritance: biallelic."

In Kuo et al (2019) reported the identification of bi-allelic CARS1 variants in four affected individuals from three families with complex syndromes that include microcephaly, developmental delay, and brittle hair and nails.

Case 1: CARS1 c.1138C>T p.(Gln380Ter) and CARS1 c.1022G>A p.(Arg341His) Case 2 and 3 (related): CARS1 c.1076C>T p.(Ser359Leu) and CARS1 c.1199T>A p. (Leu400Gln)
Case 4: Homozygous CARS1 c.2061dup p.(Ser688fs).

In-silico analysis predict that the variants result in a truncated protein or affect a highly conserved amino acid. Immunoblot analysis using CARS antibodies on protein isolated from the patient’s fibroblast confirmed the presence of a stable truncated protein for c.1138C>T nonsense variant, while the amount of full-length CARS protein was significantly reduced for the c.2061dup frameshifting variant. A possible explanation for this result is the extreme 3’ location of the variant which could allow it to escape nonsense mediated decay. Analysis of the CARS protein from Case 4 showed no change in the level of full-length CARS protein. Yeast complementation studies indicate that the p.(Gln380Ter), p. (Leu400Gln) and p.(Ser688fs) variants prevented yeast cell growth, consistent with a loss-of-function effect. Severely reduced cell growth was observed with the p.(Arg341His) and p.(Ser359Leu) variants, aminoacylation assays showed that these variants reduce enzyme activity. These results all support that each variant results in loss of function.

This report confirms that individuals with two loss of function CARS1 variants are involved in multi-system, recessive disorder that includes microcephaly, developmental delay, and brittle hair and nails. Clinical phenotypes that overlap with TTD individuals.

References: Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails. Kuo ME, et al. Am J Hum Genet, 2019 Mar 7. PMID 30824121
Sources: Expert list
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 TARS Michael Yau gene: TARS was added
gene: TARS was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Expert list
Mode of inheritance for gene: TARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TARS were set to PMID 31374204
Phenotypes for gene: TARS were set to Trichothiodystrophy 7, nonphotosensitive
Penetrance for gene: TARS were set to Complete
Mode of pathogenicity for gene: TARS 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: TARS was set to GREEN
Added comment: Name: threonyl-tRNA synthetase 1; Symbol: TARS1; HGNC ID: 11572

Current Status: Not in R227 Panel. This gene was added to the DDG2P panel in Sept 2019 as a amber gene and the reviwer noted the following: "Non-photosensitive trichothiodystrophy. Disease confidence rating in DDG2P: probable. DDG2P mutation consequence: loss of function. DDG2P allelic requirement: biallelic." Proposed change: GREEN

Supporting Evidence:
Theil et al (2021) published a multi-centre WES/WGS sequencing study which screened in a group of 24 NPS-TTD individuals with no molecular diagnosis. TTD18PV and TTD5VI are unrelated individuals initially diagnosed with TTD were found to have the following predicted pathogenic variants in the TARS1 gene:

TTD18PV: TARS1 c.826A>G p.(Lys276Glu) and TARS1 c.1912C>T p.(Arg638Ter)
TTD5VI: Homozygous TARS1 c.680T>C (p.Leu227Pro).

Testing of additional individuals with unresolved NPS-TTD by the authors did not identify any further bi-allelic variants suggesting in their cohort of 47, TARS1 variants account for 4% of NPS-TTD cases.

In-silico analysis suggest that missense variants result in amino acid substitutions that are close to the core catalytic domain of the protein which may affect its catalytic activity. Quantitative RT-PCR analysis showed only a slight reduction in total TARS mRNA levels in TTD18PV’s primary fibroblasts, while allelic-specific qRT-PCR analysis showed that 90% of the total TARS mRNA molecules are from the missense p.(Lys276Glu) TARS variant with the remaining only 10% from the c.1912C>T variant allele. Immunoblot analysis of whole-cell extracts from both patient’s fibroblasts revealed an approximate 20% reduction in the total cellular amount of full-length TARS. This is consistent with these missense variants causing protein instability.

Based on a total of 47 NPS-TTD individuals for bi-allelic TARS1 variants, the authors suggest that TARS1 variants account for 4% of NPS-TTD cases.

References: Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. Theil AF et al. Am J Hum Genet, 2019 Aug 1. PMID 31374204
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 IKZF3 Boaz Palterer edited their review of gene: IKZF3: Changed publications to: 34694366, 34155405
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 IKZF3 Boaz Palterer edited their review of gene: IKZF3: Added comment: New kindred with 4 affected subjects reported with autosomal dominant IKZF3 variant ( p.N160S ) by Kuehn et al.; Changed publications to: 34694366; Changed phenotypes to: B cell deficiency, EBV inefctions suspectibility, hypogammaglobulinemia, T and B cell abnormalities, pneumocystis pneumonia, chronic lymphocytic leukemia
Intellectual disability v3.1390 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204
Intellectual disability v3.1389 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204
Intellectual disability v3.1389 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Epiphyseal dysplasia, multiple, 2, 600204; {Intervertebral; disc disease, susceptibility to}, 603932; ?Stickler syndrome, type V, 614284 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204
Retinal disorders v2.227 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Eye Disorders to Stickler syndrome, type V, OMIM:614284
Retinal disorders v2.226 COL9A2 Arina Puzriakova Mode of inheritance for gene: COL9A2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Multiple Epiphyseal Dysplasia v1.4 COL9A2 Arina Puzriakova Publications for gene: COL9A2 were set to PMID: 20358595, PMID: 21922596, PMID: 20301302
Multiple Epiphyseal Dysplasia v1.3 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from multiple epiphyseal dysplasia; Multiple Epiphyseal Dysplasia, Dominant; Epiphyseal dysplasia, multiple, 2, 600204; {Intervertebral disc disease, susceptibility to}, 603932; Stickler syndrome, type V, 614284 to Epiphyseal dysplasia, multiple, 2, OMIM:600204
Skeletal dysplasia v2.144 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Epiphyseal dysplasia, multiple, 2 600204; Stickler syndrome, type V 614284; Stickler syndrome, type V, 614284; {Intervertebral disc disease, susceptibility to}, 603932 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204
Structural eye disease v1.85 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from STICKLER SYNDROME, TYPE V, 614284; Eye Disorders to Stickler syndrome, type V, OMIM:614284
Clefting v2.60 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from ?Stickler syndrome type V, 614284; Orofacial Clefting with skeletal features; Stickler syndrome; Cleft palate to Stickler syndrome, type V, OMIM:614284
Monogenic hearing loss v2.205 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from ?Stickler syndrome, type V, 614284 to Stickler syndrome, type V, OMIM:614284
Stickler syndrome v2.23 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from ?Stickler syndrome, type V, OMIM:614284 to Stickler syndrome, type V, OMIM:614284
Clefting v2.59 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from Stickler syndrome, type IV (ophthalmological: myopia, retinal detachment and cataracts, orofacial: micrognathia, midface hypoplasia and cleft palate, auditory:sensorineural hearing loss and articular: epiphyseal dysplasia) symptoms; Autosomal recessive Stickler syndrome; Orofacial Clefting with skeletal features; Cleft palate to Stickler syndrome, type IV, OMIM:614134
Retinal disorders v2.225 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from Eye Disorders to Stickler syndrome, type IV, OMIM:614134
Structural eye disease v1.84 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from Stickler syndrome, type IV, 614134; Eye Disorders to Stickler syndrome, type IV, OMIM:614134
Retinal disorders v2.224 COL9A1 Arina Puzriakova Mode of inheritance for gene: COL9A1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1388 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from ?Epiphyseal dysplasia, multiple, 6, 614135; Stickler syndrome, type IV, 614134 to Stickler syndrome, type IV, OMIM:614134; Epiphyseal dysplasia, multiple, 6, OMIM:614135
Long QT syndrome v2.23 ALG10 Sarah Leigh Tag new-gene-name tag was added to gene: ALG10.
Short QT syndrome v2.7 ALG10 Sarah Leigh Tag new-gene-name tag was added to gene: ALG10.
Congenital disorders of glycosylation v2.77 ALG10 Sarah Leigh commented on gene: ALG10: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least one terminating variant reported.
Congenital disorders of glycosylation v2.77 ALG10 Sarah Leigh Classified gene: ALG10 as Red List (low evidence)
Congenital disorders of glycosylation v2.77 ALG10 Sarah Leigh Added comment: Comment on list classification: Homozygous null ALG10 variant (NM_032834.4) c.1170_1171delAA (p.Lys391Valfs∗35) was found in a Turkish female, with frequent myoclonus (reported at 13 years), rare tonic-clonic seizure, ataxia, mild cognitive dysfunction (reported at 16 years) and scoliosis (PMID 33798445). PMID 33798445 also reports that a yeast alg10 deletion strain was used to re-express human wild-type and the variant ALG10 proteins for functional complementation. They found that while the yeast or human wild type strains resulted in mature reported protein, the variant strain resulted in hypo-glycosylated reporter protein.
Congenital disorders of glycosylation v2.77 ALG10 Sarah Leigh Gene: alg10 has been classified as Red List (Low Evidence).
Skeletal dysplasia v2.143 COL9A1 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: COL9A1.
Skeletal dysplasia v2.143 COL9A1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS panel update. COL9A1 is associated with two relevant disorders as they both include epiphyseal dysplasia - one of which shows biallelic inheritance (Stickler syndrome, type IV, OMIM:614134) while the other is associated with monoallelic inheritance (Epiphyseal dysplasia, multiple, 6, OMIM:614135)
Skeletal dysplasia v2.143 COL9A1 Arina Puzriakova Mode of inheritance for gene: COL9A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v2.204 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from Stickler syndrome, type IV, 614134; hearing loss to Stickler syndrome, type IV, OMIM:614134; Hearing loss
Monogenic hearing loss v2.203 COL9A1 Arina Puzriakova Mode of inheritance for gene: COL9A1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.142 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from Stickler syndrome, type IV 614134; Epiphyseal dysplasia, multiple, 6 614135 to Stickler syndrome, type IV, OMIM:614134; Epiphyseal dysplasia, multiple, 6, OMIM:614135
Infantile enterocolitis & monogenic inflammatory bowel disease v1.27 COL7A1 Arina Puzriakova Mode of inheritance for gene: COL7A1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Infantile enterocolitis & monogenic inflammatory bowel disease v1.26 COL7A1 Arina Puzriakova Classified gene: COL7A1 as Amber List (moderate evidence)
Infantile enterocolitis & monogenic inflammatory bowel disease v1.26 COL7A1 Arina Puzriakova Added comment: Comment on list classification: Internal review from the Genomics England clinical team has advised this gene be made Amber, as although there is evidence for gastrointestinal phenotypes in patients who are homozygous for variants in this gene, the skin phenotype more commonly associated with Epidermolysis bullosa is severe and would likely be picked up elsewhere.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.26 COL7A1 Arina Puzriakova Gene: col7a1 has been classified as Amber List (Moderate Evidence).
Epidermolysis bullosa v1.7 COL7A1 Arina Puzriakova Phenotypes for gene: COL7A1 were changed from Dystrophic Epidermolysis Bullosa; Epidermolysis bullosa dystrophica (AD), 131750; Epidermolysis bullosa dystrophica (AR), 226600; Epidermolysis bullosa, pretibial (AR,AD), 131850; EBD, Bart type (AD), 132000; EBD inversa (AR), 226600; Transient bullous of the newborn (AR,AD), 131705 to Epidermolysis bullosa dystrophica (AD), OMIM:131750; Epidermolysis bullosa, pretibial (AR,AD), OMIM:131850; Epidermolysis bullosa dystrophica (AR), OMIM:226600; EBD, Bart type (AD), OMIM:132000; Epidermolysis bullosa pruriginosa, OMIM:604129; Transient bullous of the newborn (AR,AD), OMIM:131705; EBD inversa (AR), OMIM:226600
Hereditary neuropathy v1.418 CPOX Ivone Leong Mode of inheritance for gene: CPOX was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.417 CPOX Ivone Leong Tag Q4_21_MOI was removed from gene: CPOX.
Early onset or syndromic epilepsy v2.449 DEAF1 Ivone Leong Tag Q4_21_MOI tag was added to gene: DEAF1.
Early onset or syndromic epilepsy v2.449 DEAF1 Ivone Leong reviewed gene: DEAF1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1387 COL6A3 Arina Puzriakova Mode of inheritance for gene: COL6A3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.742 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1; DYSTONIA 27 to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Fetal anomalies v1.741 COL6A3 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS panel update. COL6A3 is associated with two relevant disorders, both of which show biallelic and monoallelic inheritance (Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090).
Fetal anomalies v1.741 COL6A3 Arina Puzriakova Mode of inheritance for gene: COL6A3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.740 COL6A3 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: COL6A3.
Childhood onset dystonia, chorea or related movement disorder v1.162 COL6A3 Arina Puzriakova Publications for gene: COL6A3 were set to
Childhood onset dystonia, chorea or related movement disorder v1.161 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Dystonia 27, 616411 to Dystonia 27, OMIM:616411
Skeletal dysplasia v2.141 ZNF687 Adrienne Flanagan gene: ZNF687 was added
gene: ZNF687 was added to Skeletal dysplasia. Sources: Other,Research
Mode of inheritance for gene: ZNF687 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF687 were set to PMID: 29493781, PMID: 28968976, PMID: 26849110
Phenotypes for gene: ZNF687 were set to Paget Disease of Bone with associated Giant Cell Tumour.
Penetrance for gene: ZNF687 were set to unknown
Mode of pathogenicity for gene: ZNF687 was set to Other
Review for gene: ZNF687 was set to GREEN
Added comment: Missense mutation c.2810C>G (p.Pro937Arg) alters the nuclear-ctyoplasmic balance of ZNF687 by generating a stronger nuclear localisation signal thereby acting as a gain-of-function mutation.
Sources: Other, Research
Intellectual disability v3.1386 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Gene2Phenotype confirmed gene with ID HPO to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.31 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Bethlem myopathy 1 158810 to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Congenital myopathy v2.61 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Arthrogryposis v3.133 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Ullrich congenital muscular dystrophy 1 254090; Bethlem myopathy, 158810Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Congenital muscular dystrophy v2.20 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Fetal anomalies v1.740 COL6A1 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: COL6A1.
Fetal anomalies v1.740 COL6A1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS panel update. COL6A1 is associated with two relevant disorders, both of which show biallelic and monoallelic inheritance (Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090).
Fetal anomalies v1.740 COL6A1 Arina Puzriakova Mode of inheritance for gene: COL6A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.739 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from COL6A1 associated myopathy to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Arthrogryposis v3.132 COL6A1 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: COL6A1.
Arthrogryposis v3.132 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Ullrich congenital muscular dystrophy 1 254090; Bethlem myopathy 1 158810; Bethlem myopathy, 158810Ullrich congenital muscular dystrophy, 254090{Ossification of the posterior longitudinal spinal ligaments}, 602475 (2); Bethlem myopathy; Ullrich Congenital Muscular Dystrophy to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Arthrogryposis v3.131 COL6A1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS panel update. COL6A1 is associated with two relevant disorders which include multiple joint contractures, both of which show biallelic and monoallelic inheritance (Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090).
Arthrogryposis v3.131 COL6A1 Arina Puzriakova Mode of inheritance for gene: COL6A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.738 IFT122 Sarah Leigh reviewed gene: IFT122: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.738 IFT122 Sarah Leigh Publications for gene: IFT122 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.55 IFT122 Sarah Leigh Publications for gene: IFT122 were set to 24689072; 20493458
Fetal anomalies v1.737 IFT122 Sarah Leigh Phenotypes for gene: IFT122 were changed from CRANIOECTODERMAL DYSPLASIA to Cranioectodermal dysplasia type 1 OMIM:218330; cranioectodermal dysplasia 1 MONDO:0021093
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.54 IFT122 Sarah Leigh Phenotypes for gene: IFT122 were changed from cranioectodermal dysplasia; Cranioectodermal dysplasia type 1 218330 to Cranioectodermal dysplasia type 1 OMIM:218330; cranioectodermal dysplasia 1 MONDO:0021093
Intellectual disability v3.1385 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Intellectual disability v3.1384 COL6A1 Arina Puzriakova Mode of inheritance for gene: COL6A1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v2.64 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy 1,OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.30 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy 1 158810 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Congenital myopathy v2.60 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Congenital muscular dystrophy v2.19 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Intellectual disability v3.1383 COL4A4 Arina Puzriakova Mode of inheritance for gene: COL4A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Proteinuric renal disease v2.61 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Intellectual disability v3.1382 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Alport syndrome, autosomal recessive, 203780; Hematuria, familial benign to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Monogenic hearing loss v2.202 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Alport syndrome, autosomal recessive, 203780Hematuria,familial benign; Alportsyndrome,autosomalrecessive,203780Hematuria,familialbenign to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Unexplained young onset end-stage renal disease v1.23 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Hematuria,familial benign; Alport syndrome, autosomal recessive, 203780 to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Unexplained kidney failure in young people v1.99 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Alport syndrome, autosomal recessive, 203780; Hematuria,familial benign to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Cystic kidney disease v2.27 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Cystic kidney disease, MONDO:0002473 to Cystic kidney disease, MONDO:0002473
Cystic kidney disease v2.27 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from cystic kidney disease MONDO:0002473 to Cystic kidney disease, MONDO:0002473
Unexplained kidney failure in young people v1.98 COL4A4 Arina Puzriakova Added comment: Comment on mode of inheritance: Changing to BOTH monoallelic and biallelic, autosomal or pseudoautosomal because it is associated with two relevant disorders one which shows biallelic and one which shows monoallelic inheritance ( Alport syndrome 2, autosomal recessive is AR and Hematuria, familial benign is AD).
Unexplained kidney failure in young people v1.98 COL4A4 Arina Puzriakova Mode of inheritance for gene: COL4A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.417 CPOX Ivone Leong Tag Q4_21_MOI tag was added to gene: CPOX.
Hereditary neuropathy v1.417 CPOX Ivone Leong reviewed gene: CPOX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.64 CPOX Ivone Leong Tag Q4_21_MOI tag was added to gene: CPOX.
Hereditary neuropathy or pain disorder v1.64 CPOX Ivone Leong reviewed gene: CPOX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v2.141 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Stickler syndrome, type II 604841; Marshall syndrome 154780; Fibrochondrogenesis 1 228520 to Stickler syndrome, type II, OMIM:604841; Marshall syndrome, OMIM:154780; Fibrochondrogenesis 1, OMIM:228520
Clefting v2.58 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Orofacial Clefting with skeletal features; Stickler Syndrome; Cleft palate to Marshall Syndrome, OMIM:154780; Stickler syndrome, type II, OMIM:604841
Bilateral congenital or childhood onset cataracts v2.86 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Marshall Syndrome; Stickler syndrome to Marshall Syndrome, OMIM:154780; Stickler syndrome, type II, OMIM:604841
Monogenic hearing loss v2.201 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Stickler syndrome, type II, MIM#604841; Deafness, autosomal dominant 37, MIM#618533 to Deafness, autosomal dominant 37, OMIM:618533; Stickler syndrome, type II, OMIM:604841
Retinal disorders v2.223 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Eye Disorders to Stickler syndrome, type II, OMIM:604841
Cytopenia - NOT Fanconi anaemia v1.43 CLPB Dmitrijs Rots reviewed gene: CLPB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34140661; Phenotypes: Neutropenia, intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1381 CLPB Dmitrijs Rots reviewed gene: CLPB: 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: PMID: 34140661; Phenotypes: Neutropenia, intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Severe microcephaly v2.267 DPP6 Ivone Leong Tag Q4_21_expert_review tag was added to gene: DPP6.
Proteinuric renal disease v2.60 TRIM8 Ivone Leong Classified gene: TRIM8 as Amber List (moderate evidence)
Proteinuric renal disease v2.60 TRIM8 Ivone Leong Gene: trim8 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.59 TRIM8 Ivone Leong Tag Q4_21_rating tag was added to gene: TRIM8.
Proteinuric renal disease v2.59 TRIM8 Ivone Leong changed review comment from: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.; to: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Unexplained young onset end-stage renal disease v1.22 TRIM8 Ivone Leong Tag Q4_21_rating tag was added to gene: TRIM8.
Unexplained young onset end-stage renal disease v1.22 TRIM8 Ivone Leong Classified gene: TRIM8 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v1.22 TRIM8 Ivone Leong Gene: trim8 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v1.21 TRIM8 Ivone Leong changed review comment from: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.; to: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Unexplained young onset end-stage renal disease v1.21 TRIM8 Ivone Leong Entity copied from Unexplained kidney failure in young people v1.97
Unexplained young onset end-stage renal disease v1.21 TRIM8 Ivone Leong gene: TRIM8 was added
gene: TRIM8 was added to Unexplained paediatric onset end-stage renal disease. Sources: Expert Review Green,Literature
Mode of inheritance for gene: TRIM8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIM8 were set to 33508234; 32531461; 32193649; 33508234
Phenotypes for gene: TRIM8 were set to nephrotic syndrome; epilepsy; Focal segmental glomerulosclerosis and neurodevelopmental syndrome, OMIM:619428
Mode of pathogenicity for gene: TRIM8 was set to Other
Proteinuric renal disease v2.59 TRIM8 Ivone Leong Entity copied from Unexplained kidney failure in young people v1.97
Proteinuric renal disease v2.59 TRIM8 Ivone Leong gene: TRIM8 was added
gene: TRIM8 was added to Proteinuric renal disease. Sources: Expert Review Green,Literature
Mode of inheritance for gene: TRIM8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIM8 were set to 33508234; 32531461; 32193649; 33508234
Phenotypes for gene: TRIM8 were set to nephrotic syndrome; epilepsy; Focal segmental glomerulosclerosis and neurodevelopmental syndrome, OMIM:619428
Mode of pathogenicity for gene: TRIM8 was set to Other
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong Tag watchlist tag was added to gene: PI4KA.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong edited their review of gene: PI4KA: Changed rating: AMBER
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong commented on gene: PI4KA: This gene is rated Amber as not all affected individuals have IBD. Until more evidence is available this gene has been given an Amber rating.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong changed review comment from: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.; to: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong Tag Q3_21_rating was removed from gene: PI4KA.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.241
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Intellectual disability v3.1381 CDH15 Arina Puzriakova Tag Q4_21_rating tag was added to gene: CDH15.
Intellectual disability v3.1381 CDH15 Arina Puzriakova Classified gene: CDH15 as Green List (high evidence)
Intellectual disability v3.1381 CDH15 Arina Puzriakova Added comment: Comment on list classification: Gene should be demoted to Red as there is limited evidence supporting this gene-disease association. The only cases reported to date with SNVs were discovered by targeted sequencing of CDH15. Clinical information was limited, describing only mild ID in some cases. There are also multiple benign LOF variants in population databases. Asymptomatic carriers lead authors to suggest incomplete penetrance but all identified variants are in gnomAD so are unlikely to be causal.
Intellectual disability v3.1381 CDH15 Arina Puzriakova Gene: cdh15 has been classified as Green List (High Evidence).
Cerebellar hypoplasia v1.60 PI4KA Ivone Leong Classified gene: PI4KA as Green List (high evidence)
Cerebellar hypoplasia v1.60 PI4KA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene associated with a relevant phenotype in OMIM and Gene2Phenotype (confirmed). There is now enough evidence to support a gene-disease association.
Cerebellar hypoplasia v1.60 PI4KA Ivone Leong Gene: pi4ka has been classified as Green List (High Evidence).
Intellectual disability v3.1380 CDH15 Arina Puzriakova Publications for gene: CDH15 were set to
Childhood onset hereditary spastic paraplegia v2.87 PI4KA Ivone Leong edited their review of gene: PI4KA: Added comment: After consulting with the Genomics England Clinical Team it was decided that this gene should be added to the Hereditary spastic paraplegia - childhood onset panel with an Amber rating.

Helen Brittain:
"I think the spasticity is likely to be secondary to the CNS findings and therefore might opt for amber at this stage, as it is perhaps unlikely to be clearly relevant to the more typical cohort with isolated spasticity that will be targeted by that panel."; Changed rating: AMBER
Intellectual disability v3.1379 CDH15 Arina Puzriakova Phenotypes for gene: CDH15 were changed from Mental retardation, autosomal dominant 3, 612580; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 3 (MRD3) to Mental retardation, autosomal dominant 3, OMIM:612580
Childhood onset hereditary spastic paraplegia v2.87 PI4KA Ivone Leong changed review comment from: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.; to: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.
Childhood onset hereditary spastic paraplegia v2.87 PI4KA Ivone Leong Tag Q3_21_rating was removed from gene: PI4KA.
Childhood onset hereditary spastic paraplegia v2.87 PI4KA Ivone Leong Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.241
Childhood onset hereditary spastic paraplegia v2.87 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Childhood onset hereditary spastic paraplegia v2.86 GJA1 Arina Puzriakova Publications for gene: GJA1 were set to 18660473; 22214631; 29927410; 31023660; 33190326; 33612672
Childhood onset hereditary spastic paraplegia v2.85 GJA1 Arina Puzriakova commented on gene: GJA1: Regarding inclusion of this gene on the childhood-onset panel, Helen Brittain (Genomics England Clinical Team) suggests - "As you say, there are sufficient cases albeit seemingly edge cases. I would be inclined to include it on the paediatric panel, as they are outlining the spasticity as a feature of ODDD, rather than a separate clinical entity. ODDD would be a paediatric-age diagnosis to make and the fact that it is clinically recognisable could aid in interpretation of variants of uncertain significance"
Malformations of cortical development v2.94 PI4KA Ivone Leong Tag watchlist was removed from gene: PI4KA.
Tag Q4_21_rating tag was added to gene: PI4KA.
Malformations of cortical development v2.94 PI4KA Ivone Leong Publications for gene: PI4KA were set to 25855803
Malformations of cortical development v2.93 PI4KA Ivone Leong edited their review of gene: PI4KA: Added comment: There is now enough evidence to support this gene-disease association. This gene should be rated Green at the next review.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.; Changed rating: GREEN; Changed publications to: 25855803, 34415322, 34415310
Childhood onset hereditary spastic paraplegia v2.85 GJA1 Arina Puzriakova Entity copied from Hereditary spastic paraplegia - adult onset v1.73
Childhood onset hereditary spastic paraplegia v2.85 GJA1 Arina Puzriakova gene: GJA1 was added
gene: GJA1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: GJA1.
Mode of inheritance for gene: GJA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GJA1 were set to 18660473; 22214631; 29927410; 31023660; 33190326; 33612672
Phenotypes for gene: GJA1 were set to Oculodentodigital dysplasia, OMIM:164200; Spastic paraplegia
Malformations of cortical development v2.93 PI4KA Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Severe microcephaly v2.267 DYNC1I2 Ivone Leong Classified gene: DYNC1I2 as Amber List (moderate evidence)
Severe microcephaly v2.267 DYNC1I2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). There is sufficient evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.267 DYNC1I2 Ivone Leong Gene: dync1i2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.266 DYNC1I2 Ivone Leong Tag Q4_21_rating tag was added to gene: DYNC1I2.
IUGR and IGF abnormalities v1.41 ARCN1 Ivone Leong Phenotypes for gene: ARCN1 were changed from Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay, OMIM:617164
IUGR and IGF abnormalities v1.40 ARCN1 Ivone Leong Publications for gene: ARCN1 were set to PMID: 27476655; PMID: 33154040
IUGR and IGF abnormalities v1.39 ARCN1 Ivone Leong Classified gene: ARCN1 as Amber List (moderate evidence)
IUGR and IGF abnormalities v1.39 ARCN1 Ivone Leong Added comment: Comment on list classification: New gene added by Andžela Lazdāne (Children's Clinical University Hospital of Latvia). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). After consulting the Genomics England Clinical Team it was thought that this gene should be Amber on this panel for now as the skeletal phenotype in association with short stature makes the gene better suited to a skeletal panel.
IUGR and IGF abnormalities v1.39 ARCN1 Ivone Leong Gene: arcn1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.266 ARCN1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel.

The patients in the 2 additional papers (PMID: 31075182 and 33154040) do have microcephaly; however, it is not clear as to what the severity is of the patients currently (only their birth head circumferences was given, which were not severe enough for this panel, and no measurements were given at later time points).

Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel.

The patients in the 2 additional papers (PMID: 31075182 and 33154040) do have microcephaly; however, it is not clear as to what the severity is of the patients currently (only their birth head circumferences were given, which were not severe enough for this panel, and no measurements were given at later time points).

Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.
Hypertrophic cardiomyopathy v2.30 GYG1 Ivone Leong Tag Q4_21_expert_review tag was added to gene: GYG1.
Hypertrophic cardiomyopathy v2.30 GYG1 Ivone Leong Tag watchlist tag was added to gene: GYG1.
Hypertrophic cardiomyopathy v2.30 GYG1 Ivone Leong Classified gene: GYG1 as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v2.30 GYG1 Ivone Leong Added comment: Comment on list classification: New gene added by Oliver Watkinson (NHS). THis gene is associated with a phenotype in OMIM but not Gene2Phenotype. While there are >3 unrelated cases of affected patients with HCM there are other patients with variants in this gene who do not have any cardiomyopathy phenotype. As indicated by Oliver Watkinson, the sister of an affected patient had the same genotype but was unaffected. Based on the available evidence this gene has been given an Amber rating until more cases are available.
Hypertrophic cardiomyopathy v2.30 GYG1 Ivone Leong Gene: gyg1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.736 LRIT3 Zornitza Stark reviewed gene: LRIT3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Night blindness, congenital stationary (complete), 1F, autosomal recessive 615058; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.50 KPNA3 Dmitrijs Rots gene: KPNA3 was added
gene: KPNA3 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: KPNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KPNA3 were set to PMID: 34564892
Phenotypes for gene: KPNA3 were set to Infantile onset spastic paraplegia; developmental delay
Penetrance for gene: KPNA3 were set to unknown
Mode of pathogenicity for gene: KPNA3 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: KPNA3 was set to GREEN
Added comment: 8 reported families with de novo missense variants, that segregates with pure HSP with infantile onset and some functional data PMID: 34564892
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.84 KPNA3 Dmitrijs Rots gene: KPNA3 was added
gene: KPNA3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: KPNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KPNA3 were set to PMID: 34564892
Phenotypes for gene: KPNA3 were set to Infantile onset spastic paraplegia; developmental delay
Penetrance for gene: KPNA3 were set to unknown
Mode of pathogenicity for gene: KPNA3 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: KPNA3 was set to GREEN
Added comment: 8 reported families with de novo missense variants, that segregates with pure HSP with infantile onset and some functional data PMID: 34564892
Sources: Literature
Fetal anomalies v1.736 AAAS Zornitza Stark edited their review of gene: AAAS: Changed rating: RED
Fetal anomalies v1.736 AAAS Zornitza Stark reviewed gene: AAAS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Achalasia-addisonianism-alacrimia syndrome, MIM#231550; Mode of inheritance: None
Early onset or syndromic epilepsy v2.449 CELF2 Dmitrijs Rots reviewed gene: CELF2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: DEE; Mode of inheritance: None
Hereditary neuropathy or pain disorder v1.64 GBF1 Dmitrijs Rots reviewed gene: GBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial dysautonomia v1.15 DST Dmitrijs Rots reviewed gene: DST: Rating: AMBER; Mode of pathogenicity: None; Publications: PubMed: 30371979; Phenotypes: Neuropathy, hereditary sensory and autonomic; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.64 TECPR2 Dmitrijs Rots gene: TECPR2 was added
gene: TECPR2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: TECPR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TECPR2 were set to PubMed: 33847017
Phenotypes for gene: TECPR2 were set to Hereditary sensory and autonomic neuropathy
Penetrance for gene: TECPR2 were set to unknown
Review for gene: TECPR2 was set to GREEN
Added comment: Neuser et al. (2021) reported clinical findings in 17 patients, including 2 sib pairs, from 15 families segregating HSAN9.
Sources: Literature
Familial dysautonomia v1.15 TECPR2 Dmitrijs Rots reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 33847017; Phenotypes: Sensory neuropathy, autonomic neuropathy; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 DEF6 Dmitrijs Rots reviewed gene: DEF6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32562707; Phenotypes: ; Mode of inheritance: None
Cutaneous photosensitivity with a likely genetic cause v1.8 ANAPC1 Tom Cullup reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31303264; Phenotypes: Rothmund-Thomson syndrome type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v1.16 ANAPC1 Tom Cullup reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31303264; Phenotypes: Rothmund-Thomson syndrome type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v1.26 ANAPC1 Tom Cullup reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31303264; Phenotypes: Rothmund-Thomson syndrome type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v1.26 AXIN2 Tom Cullup gene: AXIN2 was added
gene: AXIN2 was added to Ectodermal dysplasia. Sources: Other
Mode of inheritance for gene: AXIN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AXIN2 were set to 15042511
Phenotypes for gene: AXIN2 were set to OLIGODONTIA-COLORECTAL CANCER SYNDROME
Penetrance for gene: AXIN2 were set to unknown
Review for gene: AXIN2 was set to GREEN
Added comment: Sources: Other
Rare genetic inflammatory skin disorders v1.40 ECM1 Tom Cullup gene: ECM1 was added
gene: ECM1 was added to Rare genetic inflammatory skin disorders. Sources: Other
Mode of inheritance for gene: ECM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ECM1 were set to 11929856
Phenotypes for gene: ECM1 were set to Urbach-Wiethe disease
Penetrance for gene: ECM1 were set to Complete
Review for gene: ECM1 was set to GREEN
Added comment: Sources: Other
Neurological ciliopathies v1.20 TMEM218 Tom Cullup reviewed gene: TMEM218: Rating: GREEN; Mode of pathogenicity: None; Publications: 33791682; Phenotypes: JOUBERT SYNDROME 39; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Multiple monogenic benign skin tumours v1.12 NOTCH3 Tom Cullup gene: NOTCH3 was added
gene: NOTCH3 was added to Multiple monogenic benign skin tumours. Sources: Other
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH3 were set to 23731542
Phenotypes for gene: NOTCH3 were set to MYOFIBROMATOSIS, INFANTILE, 2
Penetrance for gene: NOTCH3 were set to unknown
Review for gene: NOTCH3 was set to AMBER
Added comment: Request to add PDGFRB and NOTCH3 to MMBST panel - phenotype appropriate, but may need to broaden eligibility criteria simultaneously.
Sources: Other
Multiple monogenic benign skin tumours v1.12 PDGFRB Tom Cullup reviewed gene: PDGFRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23731537, 23731542; Phenotypes: MYOFIBROMATOSIS, INFANTILE, 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ichthyosis and erythrokeratoderma v1.68 ASPRV1 Tom Cullup reviewed gene: ASPRV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32516568; Phenotypes: ICHTHYOSIS, LAMELLAR, AUTOSOMAL DOMINANT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pigmentary skin disorders v1.16 NDUFB11 Tom Cullup gene: NDUFB11 was added
gene: NDUFB11 was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: NDUFB11 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: NDUFB11 were set to 33670341
Phenotypes for gene: NDUFB11 were set to Linear Skin Defects with Multiple Congenital Anomalies
Penetrance for gene: NDUFB11 were set to unknown
Review for gene: NDUFB11 was set to GREEN
Added comment: XLD - lethal in males
Sources: Other
Pigmentary skin disorders v1.16 COX7B Tom Cullup gene: COX7B was added
gene: COX7B was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: COX7B 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: COX7B were set to 33670341
Phenotypes for gene: COX7B were set to Linear Skin Defects with Multiple Congenital Anomalies
Penetrance for gene: COX7B were set to unknown
Review for gene: COX7B was set to GREEN
Added comment: XLD - lethal in males
Sources: Other
Pigmentary skin disorders v1.16 HCCS Tom Cullup gene: HCCS was added
gene: HCCS was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: HCCS 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: HCCS were set to 33670341
Phenotypes for gene: HCCS were set to Linear Skin Defects with Multiple Congenital Anomalies
Penetrance for gene: HCCS were set to unknown
Review for gene: HCCS was set to GREEN
Added comment: XLD - lethal in males
Sources: Other
Structural eye disease v1.83 ASPH Tom Cullup reviewed gene: ASPH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24768550; Phenotypes: Traboulsi syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v1.16 SMARCAL1 Tom Cullup gene: SMARCAL1 was added
gene: SMARCAL1 was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: SMARCAL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMARCAL1 were set to 11799392
Phenotypes for gene: SMARCAL1 were set to SCHIMKE IMMUNOOSSEOUS DYSPLASIA
Penetrance for gene: SMARCAL1 were set to Complete
Review for gene: SMARCAL1 was set to GREEN
Added comment: Sources: Other
Pigmentary skin disorders v1.16 DDX3X Tom Cullup gene: DDX3X was added
gene: DDX3X was added to Pigmentary skin disorders. Sources: Expert list
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 30349862
Phenotypes for gene: DDX3X were set to INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, SNIJDERS BLOK TYPE
Penetrance for gene: DDX3X were set to unknown
Review for gene: DDX3X was set to GREEN
Added comment: Sources: Expert list
Pigmentary skin disorders v1.16 USP9X Tom Cullup gene: USP9X was added
gene: USP9X was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: USP9X 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: USP9X were set to 26833328
Phenotypes for gene: USP9X were set to INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 99, SYNDROMIC, FEMALE-RESTRICTED
Penetrance for gene: USP9X were set to unknown
Review for gene: USP9X was set to GREEN
Added comment: Sources: Expert list
Pigmentary skin disorders v1.16 PHF6 Tom Cullup gene: PHF6 was added
gene: PHF6 was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: PHF6 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: PHF6 were set to 24092917
Phenotypes for gene: PHF6 were set to BORJESON-FORSSMAN-LEHMANN SYNDROME; Fine and whorled Blaschko-linear hypo or hyperpigmentation
Penetrance for gene: PHF6 were set to unknown
Review for gene: PHF6 was set to GREEN
Added comment: Sources: Expert list
Pigmentary skin disorders v1.16 TFE3 Tom Cullup gene: TFE3 was added
gene: TFE3 was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: TFE3 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: TFE3 were set to 32409512
Phenotypes for gene: TFE3 were set to Intellectual disability with pigmentary mosaicism and storage disorder-like features
Penetrance for gene: TFE3 were set to unknown
Review for gene: TFE3 was set to GREEN
Added comment: Sources: Expert list
Mosaic skin disorders - deep sequencing v1.5 PTPN11 Tom Cullup edited their review of gene: PTPN11: Added comment: Request upgrade to green in order that panel updates can be made in preparation for publication of case series, without delay waiting for next PanelApp update cycle.; Changed rating: GREEN; Changed publications to: Mosaic case series currently under publication review - expected to be published by end of 2021; Changed phenotypes to: Phakomatosis pigmentovascularis (PPV), Noonan syndrome with lentigines (LEOPARD)(151100), Speckled lentiginous naevus syndrome (deletion)
DDG2P v2.50 PLCB4 Kate Downes reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 22560091, PMID: 23315542, PMID: 28328130, PMID: 23913798; Phenotypes: Auriculocondylar syndrome 2 (OMIM: 614669); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Albinism or congenital nystagmus v1.19 CLCN7 Arina Puzriakova Classified gene: CLCN7 as Amber List (moderate evidence)
Albinism or congenital nystagmus v1.19 CLCN7 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as two individuals have been reported and with the same variant. Although there is some functional support, an additional independent case would help corroborate this association and indicate whether this is a variant specific phenotype. Different heterozygous CLCN7 variants have been linked to AD osteopetrosis.
Albinism or congenital nystagmus v1.19 CLCN7 Arina Puzriakova Gene: clcn7 has been classified as Amber List (Moderate Evidence).
Lysosomal storage disorder v1.76 CLCN7 Arina Puzriakova Classified gene: CLCN7 as Amber List (moderate evidence)
Lysosomal storage disorder v1.76 CLCN7 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as two individuals have been reported and with the same variant. Although there is some functional support, an additional independent case would help corroborate this association and indicate whether this is a variant specific phenotype. Different heterozygous CLCN7 variants have been linked to AD osteopetrosis.
Lysosomal storage disorder v1.76 CLCN7 Arina Puzriakova Gene: clcn7 has been classified as Amber List (Moderate Evidence).
Lysosomal storage disorder v1.75 CLCN7 Arina Puzriakova gene: CLCN7 was added
gene: CLCN7 was added to Lysosomal storage disorder. Sources: Literature
watchlist tags were added to gene: CLCN7.
Mode of inheritance for gene: CLCN7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN7 were set to 31155284
Phenotypes for gene: CLCN7 were set to Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541
Mode of pathogenicity for gene: CLCN7 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: CLCN7 was set to AMBER
Added comment: Nicoli et al., 2019 (PMID: 31155284) reported on two unrelated individuals from different ethnic backgrounds with the same de novo gain-of-function missense variant (c.2144A>G, p.Tyr715Cys) in the CLCN7 gene. Both children had generalised cutaneous hypopigmentation without ocular involvement, delayed myelination and motor development, and organomegaly. Biopsies showed that both probands had cytoplasmic inclusions, characteristic of those seen in lysosomal-storage disorders. Human phenotypes were recapitulated by a mouse model harbouring the knock-in Clcn7 variant.

This gene-disease relationship is listed in OMIM (MIM# 618541) but is not yet in G2P.
Sources: Literature
Albinism or congenital nystagmus v1.18 CLCN7 Arina Puzriakova gene: CLCN7 was added
gene: CLCN7 was added to Albinism or congenital nystagmus. Sources: Literature
watchlist tags were added to gene: CLCN7.
Mode of inheritance for gene: CLCN7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN7 were set to 31155284
Phenotypes for gene: CLCN7 were set to Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541
Mode of pathogenicity for gene: CLCN7 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: CLCN7 was set to AMBER
Added comment: Nicoli et al., 2019 (PMID: 31155284) reported on two unrelated individuals from different ethnic backgrounds with the same de novo gain-of-function missense variant (c.2144A>G, p.Tyr715Cys) in the CLCN7 gene. Both children had generalised cutaneous hypopigmentation without ocular involvement, delayed myelination and motor development, and organomegaly. Biopsies showed that both probands had cytoplasmic inclusions, characteristic of those seen in lysosomal-storage disorders. Human phenotypes were recapitulated by a mouse model harbouring the knock-in Clcn7 variant.

This gene-disease relationship is listed in OMIM (MIM# 618541) but is not yet in G2P.
Sources: Literature
Fetal anomalies v1.736 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from CLCN7-RELATED OSTEOPETROSIS; Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600 to CLCN7-RELATED OSTEOPETROSIS; Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600; Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541
Severe microcephaly v2.266 BRD4 Ivone Leong Phenotypes for gene: BRD4 were changed from Cornelia de Lange-like syndrome to Cornelia de Lange-like syndrome, MONDO:0016033
Severe microcephaly v2.265 BRD4 Ivone Leong Classified gene: BRD4 as Amber List (moderate evidence)
Severe microcephaly v2.265 BRD4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not OMIM. Based on the available evidence this gene has been given an Amber rating.
Severe microcephaly v2.265 BRD4 Ivone Leong Gene: brd4 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.264 BRD4 Ivone Leong Tag watchlist tag was added to gene: BRD4.
Hydrocephalus v2.123 HYLS1 Ivone Leong Tag Q4_21_expert_review tag was added to gene: HYLS1.
Hydrocephalus v2.123 TNFRSF11A Ivone Leong Classified gene: TNFRSF11A as Amber List (moderate evidence)
Hydrocephalus v2.123 TNFRSF11A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. Based on the expert review there is enough evidnece for this gene to be Green on this panel.
Hydrocephalus v2.123 TNFRSF11A Ivone Leong Gene: tnfrsf11a has been classified as Amber List (Moderate Evidence).
Hydrocephalus v2.122 TNFRSF11A Ivone Leong Tag Q4_21_rating tag was added to gene: TNFRSF11A.
Intellectual disability v3.1378 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4, 611490; Osteopetrosis, autosomal dominant 2, 166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Intellectual disability v3.1377 CLCN7 Arina Puzriakova Mode of inheritance for gene: CLCN7 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.480 CLCN7 Arina Puzriakova Mode of inheritance for gene: CLCN7 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.479 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Primary immunodeficiency or monogenic inflammatory bowel disease v2.479 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Defects in Intrinsic and Innate Immunity; Osteopetrosis with hypocalcemia, neurologic features to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Fetal anomalies v1.735 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from CLCN7-RELATED OSTEOPETROSIS to CLCN7-RELATED OSTEOPETROSIS; Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Fetal anomalies v1.734 CLCN7 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Biallelic' to 'Both mono- and biallelic' at the next review. At least 2 recessive cases and >3 dominant cases reported with osteopetrosis.
Fetal anomalies v1.734 CLCN7 Arina Puzriakova Mode of inheritance for gene: CLCN7 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.733 CLCN7 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN7.
Skeletal dysplasia v2.140 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4 611490; Osteopetrosis, autosomal dominant 2 166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Osteopetrosis v1.27 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4 OMIM:611490; Osteopetrosis, autosomal dominant 2 OMIM:166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Intellectual disability v3.1376 BLOC1S1 Ivone Leong Tag watchlist tag was added to gene: BLOC1S1.
Early onset or syndromic epilepsy v2.449 ARFGEF1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. ID in patients ranged from mild to moderate, which does not satisfy the criteria for this panel (moderate to severe); however, as this is one of the presenting features this gene has will be recommended to be Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Early onset or syndromic epilepsy v2.449 ARFGEF1 Ivone Leong Entity copied from Intellectual disability v3.1376
Early onset or syndromic epilepsy v2.449 ARFGEF1 Ivone Leong gene: ARFGEF1 was added
gene: ARFGEF1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: ARFGEF1.
Mode of inheritance for gene: ARFGEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARFGEF1 were set to 34113008
Phenotypes for gene: ARFGEF1 were set to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1376 ARFGEF1 Ivone Leong Phenotypes for gene: ARFGEF1 were changed from Intellectual disability; Epilepsy to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Classified gene: ARFGEF1 as Amber List (moderate evidence)
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. ID in patients ranged from mild to moderate, which does not satisfy the criteria for this panel (moderate to severe); however, as this is one of the presenting features this gene has will be recommended to be Green at the next review.
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Gene: arfgef1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1374 ARFGEF1 Ivone Leong Tag Q4_21_rating tag was added to gene: ARFGEF1.
Skeletal dysplasia v2.139 TMEM251 Eleanor Williams Classified gene: TMEM251 as Amber List (moderate evidence)
Skeletal dysplasia v2.139 TMEM251 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 2 cases reported.
Skeletal dysplasia v2.139 TMEM251 Eleanor Williams Gene: tmem251 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.138 TMEM251 Eleanor Williams Phenotypes for gene: TMEM251 were changed from Dysostosis multiplex‐like skeletal dysplasia; severe short stature to Dysostosis multiplex, Ain-Naz type, OMIM:19345; severe short stature
Skeletal dysplasia v2.137 TMEM251 Eleanor Williams reviewed gene: TMEM251: Rating: AMBER; Mode of pathogenicity: None; Publications: 33252156; Phenotypes: Dysostosis multiplex, Ain-Naz type, OMIM:19345; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.50 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from HEREDITARY SENSORY & AUTONOMIC NEUROPATHY TYPE VIII 616488 to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Hereditary neuropathy v1.417 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from hereditary sensory & autonomic neuropathy type VIII to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Hereditary neuropathy or pain disorder v1.64 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from hereditary sensory & autonomic neuropathy type VIII to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Intellectual disability v3.1374 PRDM12 Sarah Leigh Mode of inheritance for gene: PRDM12 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1373 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from NA to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Intellectual disability v3.1372 PRDM12 Sarah Leigh Publications for gene: PRDM12 were set to
Fetal anomalies v1.733 EHBP1L1 Sarah Leigh Tag Q4_21_rating tag was added to gene: EHBP1L1.
Likely inborn error of metabolism v2.188 EHBP1L1 Sarah Leigh Tag Q4_21_rating tag was added to gene: EHBP1L1.
Fetal anomalies v1.733 EHBP1L1 Sarah Leigh Entity copied from Fetal hydrops v1.39
Fetal anomalies v1.733 EHBP1L1 Sarah Leigh gene: EHBP1L1 was added
gene: EHBP1L1 was added to Fetal anomalies. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: EHBP1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EHBP1L1 were set to 34645488; 26833786; https://dmdd.org.uk/mutants/Ehbp1l1
Phenotypes for gene: EHBP1L1 were set to non-immune hydrops fetalis MONDO:0009369
Penetrance for gene: EHBP1L1 were set to unknown
Likely inborn error of metabolism v2.188 EHBP1L1 Sarah Leigh Entity copied from Fetal hydrops v1.39
Likely inborn error of metabolism v2.188 EHBP1L1 Sarah Leigh gene: EHBP1L1 was added
gene: EHBP1L1 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: EHBP1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EHBP1L1 were set to 34645488; 26833786; https://dmdd.org.uk/mutants/Ehbp1l1
Phenotypes for gene: EHBP1L1 were set to non-immune hydrops fetalis MONDO:0009369
Penetrance for gene: EHBP1L1 were set to unknown
Fetal hydrops v1.39 EHBP1L1 Sarah Leigh Publications for gene: EHBP1L1 were set to 34645488
Fetal hydrops v1.38 EHBP1L1 Sarah Leigh edited their review of gene: EHBP1L1: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least two variants reported in two unrelated families with non-immune hydrops fetalis (NIHF) resulting in recurrent fetal loss. Two Ehbp1l1−/− mouse models shared phenotypic features with the affected patients, including early death, abnormal intestinal microvilli, subcutaneous edema, perimembraneous ventricular septic defect, and thin myocardium (PMID 26833786, https://dmdd.org.uk/mutants/Ehbp1l1).; Changed rating: GREEN
Fetal hydrops v1.38 EHBP1L1 Sarah Leigh Publications for gene: EHBP1L1 were set to PMID: 34645488
Fetal hydrops v1.37 EHBP1L1 Sarah Leigh Phenotypes for gene: EHBP1L1 were changed from Non immune hydrops to non-immune hydrops fetalis MONDO:0009369
Fetal hydrops v1.36 EHBP1L1 Sarah Leigh Classified gene: EHBP1L1 as Amber List (moderate evidence)
Fetal hydrops v1.36 EHBP1L1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Fetal hydrops v1.36 EHBP1L1 Sarah Leigh Gene: ehbp1l1 has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v2.29 GYG1 Ivone Leong Phenotypes for gene: GYG1 were changed from to ?Glycogen storage disease XV, OMIM:613507; hypertrophic cardiomyopathy, MONDO:0005045
Hypertrophic cardiomyopathy v2.28 GYG1 Ivone Leong Publications for gene: GYG1 were set to 27718144
Hypertrophic cardiomyopathy v2.27 GYG1 Oliver Watkinson reviewed gene: GYG1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27718144, 20357282, 31628455; Phenotypes: Hypertrophic Cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy v2.27 GYG1 Oliver Watkinson gene: GYG1 was added
gene: GYG1 was added to Hypertrophic cardiomyopathy - teen and adult. Sources: Literature
Mode of inheritance for gene: GYG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GYG1 were set to 27718144
Penetrance for gene: GYG1 were set to Incomplete
DDG2P v2.49 ATN1 Dmitrijs Rots Deleted their review
DDG2P v2.49 ATN1 Dmitrijs Rots Deleted their comment
DDG2P v2.49 ATN1 Dmitrijs Rots reviewed gene: ATN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.50 IFT140 Sarah Leigh changed review comment from: Two IFT140 variants reported in a case of primary ciliary dyskinesia (PMID 34556108).
Sources: Literature; to: Two rare missense IFT140 variants (p.Leu693Phe & p.Lys390Arg) reported in a case of primary ciliary dyskinesia, both variats predicted to be benign by Polyphen & SIFT (PMID 34556108).
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.50 IFT140 Sarah Leigh gene: IFT140 was added
gene: IFT140 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: IFT140 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT140 were set to 34556108
Phenotypes for gene: IFT140 were set to Short-rib thoracic dysplasia 9 with or without polydactyly OMIM:266920
Review for gene: IFT140 was set to RED
Added comment: Two IFT140 variants reported in a case of primary ciliary dyskinesia (PMID 34556108).
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.49 PLK4 Sarah Leigh Publications for gene: PLK4 were set to 22503633; 34556108
Respiratory ciliopathies including non-CF bronchiectasis v1.48 PLK4 Sarah Leigh gene: PLK4 was added
gene: PLK4 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: PLK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK4 were set to 22503633; 34556108
Phenotypes for gene: PLK4 were set to Microcephaly and chorioretinopathy, autosomal recessive 2 OMIM:616171; microcephaly and chorioretinopathy 2 MONDO:0014516
Review for gene: PLK4 was set to RED
Added comment: Two PLK4 variants reported in a case of primary ciliary dyskinesia (PMID: 34556108).
Sources: Literature
Intellectual disability v3.1371 ZC4H2 Ivone Leong reviewed gene: ZC4H2: Rating: ; 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)
Intellectual disability v3.1371 ZC4H2 Ivone Leong Tag Q4_21_MOI tag was added to gene: ZC4H2.
Fetal anomalies v1.732 ZC4H2 Ivone Leong Publications for gene: ZC4H2 were set to
Fetal anomalies v1.731 ZC4H2 Ivone Leong Phenotypes for gene: ZC4H2 were changed from ARTHROGRYPOSIS MULTIPLEX CONGENITA AND INTELLECTUAL DISABILITY to Wieacker-Wolff syndrome, OMIM:314580; Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Arthrogryposis v3.130 ZC4H2 Ivone Leong Phenotypes for gene: ZC4H2 were changed from Wieacker-Wolff syndrome 314580 to Wieacker-Wolff syndrome, OMIM:314580; Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Intellectual disability v3.1371 ZC4H2 Ivone Leong Phenotypes for gene: ZC4H2 were changed from ARTHROGRYPOSIS MULTIPLEX CONGENITA AND INTELLECTUAL DISABILITY to Wieacker-Wolff syndrome, OMIM:314580; Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Infantile enterocolitis & monogenic inflammatory bowel disease v1.24 XIAP Ivone Leong Publications for gene: XIAP were set to 21173700; 17080092; 27537055 - pathogenic variant in this gene reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease; 32686289; 25943627; 24942515; 29501442
Infantile enterocolitis & monogenic inflammatory bowel disease v1.23 XIAP Ivone Leong Added comment: Comment on publications: Previously: 27537055 - pathogenic variant in this gene reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease
Infantile enterocolitis & monogenic inflammatory bowel disease v1.23 XIAP Ivone Leong Publications for gene: XIAP were set to 21173700; 17080092; 27537055 - pathogenic variant in this gene reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease.
Gastrointestinal epithelial barrier disorders v1.61 XIAP Ivone Leong Publications for gene: XIAP were set to 21173700; 17080092; 27537055
Gastrointestinal epithelial barrier disorders v1.60 XIAP Ivone Leong reviewed gene: XIAP: Rating: ; Mode of pathogenicity: None; Publications: 32686289, 25943627, 24942515, 29501442; Phenotypes: ; Mode of inheritance: None
Infantile enterocolitis & monogenic inflammatory bowel disease v1.22 XIAP Ivone Leong reviewed gene: XIAP: Rating: ; Mode of pathogenicity: None; Publications: 32686289, 25943627, 24942515, 29501442; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.478 XIAP Ivone Leong Publications for gene: XIAP were set to 26581487; 21119115; 23973892; 17080092; 21173700; 22228567; 23131490; 25943627; 31754776
Primary immunodeficiency or monogenic inflammatory bowel disease v2.477 XIAP Ivone Leong reviewed gene: XIAP: Rating: ; Mode of pathogenicity: None; Publications: 32686289, 25943627, 24942515, 29501442; Phenotypes: ; Mode of inheritance: None
Intracerebral calcification disorders v1.30 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 17617514 - identification of AP1S2 variants in a large 4-generation French family, and a Scottish family, marked calcifications of the basal ganglia were reported in affected individuals in both families; 18428203 - an additional two families reported "Studying four patients in two unrelated families in which AP1S2 nonsense and splicesite
mutations segregated, we found that affected individuals presented, in addition to previously described features,
with elevated protein levels in cerebrospinal fluid (CSF). Moreover, computed tomography scans demonstrated that
the basal ganglia calcifications associated with AP1S2 mutations appeared during childhood and might be
progressive. Based on these observations, we propose that AP1S2 mutations are responsible for a clinically
recognizable XLMR and autism syndrome associating hypotonia, delayed walking, speech delay, aggressive
behavior, brain calcifications, and elevated CSF protein levels."
Structural basal ganglia disorders v1.22 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 23756445; 17617514; 18428203
White matter disorders and cerebral calcification - narrow panel v1.208 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 17617514; 1842820
Childhood onset dystonia, chorea or related movement disorder v1.160 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 23756445; 17617514; 18428203
Intellectual disability v3.1370 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to
Hydrocephalus v2.122 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 17186471
Fetal anomalies v1.730 AP1S2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: AP1S2.
Fetal anomalies v1.730 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from MENTAL RETARDATION X-LINKED TYPE 59 to Pettigrew syndrome, OMIM:304340
Fetal anomalies v1.729 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Fetal anomalies v1.729 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Childhood onset dystonia, chorea or related movement disorder v1.159 AP1S2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: AP1S2.
Intellectual disability v3.1369 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Intellectual disability v3.1369 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Childhood onset dystonia, chorea or related movement disorder v1.159 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Childhood onset dystonia, chorea or related movement disorder v1.159 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1368 AP1S2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: AP1S2.
Structural basal ganglia disorders v1.21 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'XL, biallelic in females' to 'XL, monoallelic in females'.

Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Structural basal ganglia disorders v1.21 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 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)
Adult onset dystonia, chorea or related movement disorder v1.125 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'XL, biallelic in females' to 'XL, monoallelic in females'.

Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females.
Adult onset dystonia, chorea or related movement disorder v1.125 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 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)
Hydrocephalus v2.121 AP1S2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: AP1S2.
Hydrocephalus v2.121 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Hydrocephalus v2.121 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare multisystem ciliopathy disorders v1.148 TBC1D32 Ivone Leong Classified gene: TBC1D32 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.148 TBC1D32 Ivone Leong Gene: tbc1d32 has been classified as Green List (High Evidence).
Malformations of cortical development v2.93 TBC1D32 Ivone Leong Tag Q3_21_rating tag was added to gene: TBC1D32.
Malformations of cortical development v2.93 TBC1D32 Ivone Leong Entity copied from Rare multisystem ciliopathy disorders v1.147
Malformations of cortical development v2.93 TBC1D32 Ivone Leong gene: TBC1D32 was added
gene: TBC1D32 was added to Malformations of cortical development. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Amber
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556; 24285566
Phenotypes for gene: TBC1D32 were set to Orofaciodigital syndrome, MONDO:0015375
Penetrance for gene: TBC1D32 were set to Complete
Ophthalmological ciliopathies v1.25 TBC1D32 Ivone Leong Tag Q3_21_rating tag was added to gene: TBC1D32.
Ophthalmological ciliopathies v1.25 TBC1D32 Ivone Leong Phenotypes for gene: TBC1D32 were changed from No OMIM phenotype; Oro-facio-digital syndrome type IX (Adly (2014) Hum Mutat 35, 36) to Orofaciodigital syndrome, MONDO:0015375
Ophthalmological ciliopathies v1.24 TBC1D32 Ivone Leong Publications for gene: TBC1D32 were set to
Ophthalmological ciliopathies v1.23 TBC1D32 Ivone Leong Classified gene: TBC1D32 as Amber List (moderate evidence)
Ophthalmological ciliopathies v1.23 TBC1D32 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with Ciliopathy syndrome in Gene2Phenotype (possible) but not a phenotype in OMIM. There is enough evidence for this gene to be Green.

Green review from Rhiannon Mellis (Great Ormond Street Hospital) on the Rare multisystem ciliopathy disorders panel (ID: 150):

"The same group who reported the first individual with a ciliopathy phenotype (Adly et al 2014) now report two further unrelated fetal cases (Alsahan 2020, Monies et al 2019) with OFD/ciliopathy phenotype:

- One had polyhydramnios, hydrocephaly with enlarged biparietal diameter and dilated lateral ventricles, single nostril, anophthalmia, short long bones and echogenic lungs
- The other had holoprosencephaly, cyclops, cleft lip, ventricular septal defect, agenesis of corpus callosum, and club feet

- There are also two sib pairs (one Finnish, one Pakistani) reported by Hietamaki et al 2020 with TBC1D32 variants and a variable phenotype of pituitary hypoplasia +/- other midline defects, hydrocephalus, short limbs, polydactyly
Created: 6 Oct 2020, 3:14 p.m. | Last Modified: 6 Oct 2020, 3:14 p.m.
Panel Version: 1.129

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
OFD IX

Publications

PMID: 32573025
31130284
32060556"
Ophthalmological ciliopathies v1.23 TBC1D32 Ivone Leong Gene: tbc1d32 has been classified as Amber List (Moderate Evidence).
Hydrocephalus v2.120 TBC1D32 Ivone Leong Tag Q4_21_rating tag was added to gene: TBC1D32.
Hydrocephalus v2.120 TBC1D32 Ivone Leong Entity copied from Rare multisystem ciliopathy disorders v1.147
Hydrocephalus v2.120 TBC1D32 Ivone Leong gene: TBC1D32 was added
gene: TBC1D32 was added to Hydrocephalus. Sources: Expert list,Radboud University Medical Center, Nijmegen,Expert Review Amber
Mode of inheritance for gene: TBC1D32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556; 24285566
Phenotypes for gene: TBC1D32 were set to Orofaciodigital syndrome, MONDO:0015375
Penetrance for gene: TBC1D32 were set to Complete
Rare multisystem ciliopathy disorders v1.147 TBC1D32 Ivone Leong Classified gene: TBC1D32 as Amber List (moderate evidence)
Rare multisystem ciliopathy disorders v1.147 TBC1D32 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with Ciliopathy syndrome in Gene2Phenotype (possible) but not a phenotype in OMIM. There is enough evidence for this gene to be Green.
Rare multisystem ciliopathy disorders v1.147 TBC1D32 Ivone Leong Gene: tbc1d32 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.241 B4GAT1 Ivone Leong reviewed gene: B4GAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.241 B4GAT1 Ivone Leong Publications for gene: B4GAT1 were set to 23359570
Ataxia and cerebellar anomalies - narrow panel v2.240 B4GAT1 Ivone Leong Tag Q3_21_rating tag was added to gene: B4GAT1.
Hereditary ataxia with onset in adulthood v2.90 B4GAT1 Ivone Leong reviewed gene: B4GAT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia with onset in adulthood v2.90 B4GAT1 Ivone Leong Publications for gene: B4GAT1 were set to
Retinal disorders v2.222 ARL3 Ivone Leong edited their review of gene: ARL3: Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype (possible - RP, and probable - Joubert syndrome). There is enough evidence to support a gene-disease association for both MOIs. This gene should be rated as Green at the next review.; Changed rating: GREEN
Retinal disorders v2.222 ARL3 Ivone Leong Tag Q4_21_rating tag was added to gene: ARL3.
Retinal disorders v2.222 ARL3 Ivone Leong Mode of inheritance for gene: ARL3 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v2.221 ARL3 Ivone Leong Phenotypes for gene: ARL3 were changed from to Joubert syndrome 35, OMIM:61816; cone-rod dystrophy, MONDO:0015993; Retinitis pigmentosa 83, OMIM:618173
Retinal disorders v2.220 ARL3 Ivone Leong Added comment: Comment on publications: PMID:30269812 describes 2 unrelated consanguineous families (Saudi and Pakistani). Both have phenotype resembling Joubert syndrome (night blindness, rod-cone dystrophy, mild dysmorphic features, hypotonia (only in 1 family), ataxia, cerebellar vernis hypoplasia). Both are homozygous missense for the same amino acid residue (R149C, R149H). The authors performed some in vitro functional analysis.

PMID:16565502 describes a knockout mouse model of Arl3. The homozygous knockouts developed ciliary disease affecting kidney, biliary tract, pancreas and retina. However, there was no mention of a brain phenotype.

PMID:31743939 describes 2 large consanguineous Pakastani families with the same homozygous variant (Arg99Ile). There are 8 affected individuals in total and 7/8 had cone-rod dystrophy and no features of Joubert syndrome.

PMID:33748123 describes a Chinese family. Proband is compound het (c.91A>G, p.T31A; c.353G>T, p.C118F) and has retinal dystrophy. Heterozygous father has late onset and mild rode-cone dystrophy. Mother and sister (het) are normal. All family members did not have any other phenotypes.

PMID:26964041 describes a family with affected mother, son and daughter with retinitis pigmentosa. Affected patients were heterozygosity for Y90C. The mother's parents do not have the variant suggesting that it is a de novo event in the mother. No functional studies of the variant were performed.

PMID:30932721 reports a case where a patient has a de novo Y90C variant and has RP.

PMID:34485303 reports a heterozygous Asp67Val variant segregating in an Ashkenazi Jewish family with a dominant inherited retinal degenerations.
Retinal disorders v2.220 ARL3 Ivone Leong Publications for gene: ARL3 were set to
Ophthalmological ciliopathies v1.22 ARL3 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from Biallelic to Both monoallelic and biallelic as eye phenotype is seen for both MOIs.
Ophthalmological ciliopathies v1.22 ARL3 Ivone Leong Mode of inheritance for gene: ARL3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ophthalmological ciliopathies v1.21 ARL3 Ivone Leong Phenotypes for gene: ARL3 were changed from Joubert syndrome 35, OMIM:61816 to Joubert syndrome 35, OMIM:61816; cone-rod dystrophy, MONDO:0015993; Retinitis pigmentosa 83, OMIM:618173
Ophthalmological ciliopathies v1.20 ARL3 Ivone Leong Tag watchlist was removed from gene: ARL3.
Tag Q4_21_rating tag was added to gene: ARL3.
Ophthalmological ciliopathies v1.20 ARL3 Ivone Leong Entity copied from Neurological ciliopathies v1.20
Ophthalmological ciliopathies v1.20 ARL3 Ivone Leong gene: ARL3 was added
gene: ARL3 was added to Ophthalmological ciliopathies. Sources: Expert list,Expert Review Amber
watchlist tags were added to gene: ARL3.
Mode of inheritance for gene: ARL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL3 were set to 30269812; 16565502; 33748123; 31743939; 26964041; 30932721; 34485303
Phenotypes for gene: ARL3 were set to Joubert syndrome 35, OMIM:61816
Neurological ciliopathies v1.20 ARL3 Ivone Leong Classified gene: ARL3 as Amber List (moderate evidence)
Neurological ciliopathies v1.20 ARL3 Ivone Leong Added comment: Comment on list classification: New gene submitted by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (possible - RP, and probable - Joubert syndrome).

As there are only 2 cases that have been associated with Joubert syndrome (PMID:30269812) and the knockout mouse model does not appear to have a neurological phenotype (PMID:16565502) this gene has been given an Amber rating until further evidence is available.
Neurological ciliopathies v1.20 ARL3 Ivone Leong Gene: arl3 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v1.19 ARL3 Ivone Leong Tag watchlist tag was added to gene: ARL3.
Neurological ciliopathies v1.19 ARL3 Ivone Leong Added comment: Comment on publications: PMID:30269812 describes 2 unrelated consanguineous families (Saudi and Pakistani). Both have phenotype resembling Joubert syndrome (night blindness, rod-cone dystrophy, mild dysmorphic features, hypotonia (only in 1 family), ataxia, cerebellar vernis hypoplasia). Both are homozygous missense for the same amino acid residue (R149C, R149H). The authors performed some in vitro functional analysis.

PMID:16565502 describes a knockout mouse model of Arl3. The homozygous knockouts developed ciliary disease affecting kidney, biliary tract, pancreas and retina. However, there was no mention of a brain phenotype.

PMID:31743939 describes 2 large consanguineous Pakastani families with the same homozygous variant (Arg99Ile). There are 8 affected individuals in total and 7/8 had cone-rod dystrophy and no features of Joubert syndrome.

PMID:33748123 describes a Chinese family. Proband is compound het (c.91A>G, p.T31A; c.353G>T, p.C118F) and has retinal dystrophy. Heterozygous father has late onset and mild rode-cone dystrophy. Mother and sister (het) are normal. All family members did not have any other phenotypes.

PMID:26964041 describes a family with affected mother, son and daughter with retinitis pigmentosa. Affected patients were heterozygosity for Y90C. The mother's parents do not have the variant suggesting that it is a de novo event in the mother. No functional studies of the variant were performed.

PMID:30932721 reports a case where a patient has a de novo Y90C variant and has RP.

PMID:34485303 reports a heterozygous Asp67Val variant segregating in an Ashkenazi Jewish family with a dominant inherited retinal degenerations.
Neurological ciliopathies v1.19 ARL3 Ivone Leong Publications for gene: ARL3 were set to 30269812; 16565502
Adult onset dystonia, chorea or related movement disorder v1.124 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5 304340; Dystonia to Pettigrew syndrome, OMIM:304340
Adult onset neurodegenerative disorder v2.201 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Dystonia; Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340
Hereditary ataxia with onset in adulthood v2.89 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5 OMIM:304340; syndromic X-linked intellectual disability 5 MONDO:0010574 to Pettigrew syndrome, OMIM:304340
Intracerebral calcification disorders v1.29 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Calcifications in basal ganglia to Pettigrew syndrome, OMIM:304340; Calcifications in basal ganglia
Hereditary ataxia v1.245 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340
Ataxia and cerebellar anomalies - narrow panel v2.240 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340
White matter disorders and cerebral calcification - narrow panel v1.207 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Calcifications in basal ganglia; Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340; Calcifications in basal ganglia
Childhood onset dystonia, chorea or related movement disorder v1.158 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Dystonia; Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340; Dystonia
Intellectual disability v3.1368 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic, Fried type, 300630; MENTAL RETARDATION X-LINKED TYPE 59 (MRX59) to Pettigrew syndrome, OMIM:304340
Structural basal ganglia disorders v1.20 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5 304340 to Pettigrew syndrome, OMIM:304340
Hydrocephalus v2.119 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, OMIM:304340 to Pettigrew syndrome, OMIM:304340
Congenital muscular dystrophy v2.18 MYMK Ivone Leong commented on gene: MYMK
Congenital muscular dystrophy v2.18 MYMK Ivone Leong Tag Q3_21_expert_review tag was added to gene: MYMK.
Tag Q3_21_phenotype tag was added to gene: MYMK.
Primary ovarian insufficiency v1.51 GGPS1 Ivone Leong Classified gene: GGPS1 as Green List (high evidence)
Primary ovarian insufficiency v1.51 GGPS1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green according to my previous review.
Primary ovarian insufficiency v1.51 GGPS1 Ivone Leong Gene: ggps1 has been classified as Green List (High Evidence).
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype.

PMID:32403198 all 6 unrelated families are from different ethnic backgrounds and all had missense variants (hom or compound het). All have muscle dystrophy, contractures were noted in the more severe patients (4/11), 10/11 hearing loss, 3/3 affected females have ovariant insufficiency (other 3 females are undetermined due to age), 8/10 failure to thrive/short stature.

There is enough evidence to support a gene-disease association. This gene should be Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype.

PMID:32403198 all 6 unrelated families are from different ethnic backgrounds and all had missense variants (hom or compound het). All have muscle dystrophy, contractures were noted in the more severe patients (4/11), 10/11 hearing loss, 3/3 affected females have ovariant insufficiency (other 3 females are undetermined due to age), 8/10 failure to thrive/short stature.

There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong Tag Q4_21_rating was removed from gene: GGPS1.
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong Entity copied from Congenital muscular dystrophy v2.18
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong gene: GGPS1 was added
gene: GGPS1 was added to Primary ovarian insufficiency. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: GGPS1.
Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GGPS1 were set to 32403198
Phenotypes for gene: GGPS1 were set to Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, OMIM:619518
Monogenic hearing loss v2.200 GGPS1 Ivone Leong Entity copied from Congenital muscular dystrophy v2.18
Monogenic hearing loss v2.200 GGPS1 Ivone Leong gene: GGPS1 was added
gene: GGPS1 was added to Hearing loss. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: GGPS1.
Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GGPS1 were set to 32403198
Phenotypes for gene: GGPS1 were set to Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, OMIM:619518
Congenital muscular dystrophy v2.18 GGPS1 Ivone Leong Tag Q4_21_rating tag was added to gene: GGPS1.
Congenital muscular dystrophy v2.18 GGPS1 Ivone Leong Classified gene: GGPS1 as Amber List (moderate evidence)
Congenital muscular dystrophy v2.18 GGPS1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype.

PMID:32403198 all 6 unrelated families are from different ethnic backgrounds and all had missense variants (hom or compound het). All have muscle dystrophy, contractures were noted in the more severe patients (4/11), 10/11 hearing loss, 3/3 affected females have ovariant insufficiency (other 3 females are undetermined due to age), 8/10 failure to thrive/short stature.

There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Congenital muscular dystrophy v2.18 GGPS1 Ivone Leong Gene: ggps1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v2.17 GGPS1 Ivone Leong Phenotypes for gene: GGPS1 were changed from Muscular dystrophy; Deafness; Ovarian insufficiency to Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, OMIM:619518
Paediatric or syndromic cardiomyopathy v1.57 GSN Ivone Leong Classified gene: GSN as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.57 GSN Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is associated with a phenotype in OMIM and Gene2Phenotype.

PMID: 26339870 found that 12/227 patients had cardiomyopathy and previous case reports and publications show that cardiomyopathy is only present in some cases and the age of diagnosis (or when pacemakers were implants into patients) is >50 years. Cardiomyopathy does not appear to be a presenting feature.

Therefore, this gene has been given an Amber rating.
Paediatric or syndromic cardiomyopathy v1.57 GSN Ivone Leong Gene: gsn has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1367 BLOC1S1 Dmitrijs Rots gene: BLOC1S1 was added
gene: BLOC1S1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to PMID: 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Review for gene: BLOC1S1 was set to GREEN
Added comment: 4 cases with similar phenotype and inheritance reported
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v1.57 MYH1 Dmitrijs Rots gene: MYH1 was added
gene: MYH1 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Mode of inheritance for gene: MYH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYH1 were set to PMID: 33755318
Phenotypes for gene: MYH1 were set to Rhabdomyolysis
Penetrance for gene: MYH1 were set to unknown
Mode of pathogenicity for gene: MYH1 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: MYH1 was set to AMBER
Added comment: One patient reported with some statistical evidence and known horse "model" with same phenotype.
Sources: Literature
Fetal hydrops v1.35 EHBP1L1 Dmitrijs Rots gene: EHBP1L1 was added
gene: EHBP1L1 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: EHBP1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EHBP1L1 were set to PMID: 34645488
Phenotypes for gene: EHBP1L1 were set to Non immune hydrops
Penetrance for gene: EHBP1L1 were set to unknown
Review for gene: EHBP1L1 was set to GREEN
Added comment: 2 families with confirming mouse data
Sources: Literature
Intellectual disability v3.1367 FAAH2 Dmitrijs Rots reviewed gene: FAAH2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34645488; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1367 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Biallelic' only. Mild cognitive impairment has been reported in some patients with CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ID. There is also controversy regarding any link between CLCN2 and epilepsy.
Intellectual disability v3.1367 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.448 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628 to {Epilepsy, juvenile myoclonic, susceptibility to, 8}, OMIM:607628; {Epilepsy, juvenile absence, susceptibility to, 2}, OMIM:607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, OMIM:607628
Intellectual disability v3.1366 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628 to Leukoencephalopathy with ataxia, OMIM:615651
Intellectual disability v3.1365 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 23707145; 19191339
Early onset or syndromic epilepsy v2.447 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Monoallelic' only. Seizures have been linked with monoallelic variants (MIM# 607628) although there is debate regarding this gene-disease relationship, hence the current Red rating on this panel. Autosomal recessive pathogenic variants are also associated with Leukoencephalopathy (MIM# 615651) which does not include epilepsy.
Early onset or syndromic epilepsy v2.447 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult onset neurodegenerative disorder v2.200 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only. Features of neurodegeneration are seen in CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes are relevant to this panel.
Adult onset neurodegenerative disorder v2.200 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v2.199 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from {Epilepsy, juvenile absence, susceptibility to, 2}, OMIM:607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, OMIM:607628; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, OMIM:607628; Leukoencephalopathy with ataxia, OMIM:615651 to Leukoencephalopathy with ataxia, OMIM:615651
Hereditary ataxia with onset in adulthood v2.88 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628; Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628 to Leukoencephalopathy with ataxia, OMIM:615651
Hereditary ataxia v1.244 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628 to Leukoencephalopathy with ataxia, OMIM:615651
Adult onset neurodegenerative disorder v2.198 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 19191339; 23707145
Adult onset neurodegenerative disorder v2.197 CLCN2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN2.
Familial Meniere Disease v1.1 AQP6 Eldar Dedic reviewed gene: AQP6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Familial Meniere Disease v1.1 AQP5 Eldar Dedic reviewed gene: AQP5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Hereditary ataxia with onset in adulthood v2.87 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 23707145; 19191339
Hereditary ataxia v1.243 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 23707145; 19191339
Ataxia and cerebellar anomalies - narrow panel v2.239 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 19191339; 23707145
Ataxia and cerebellar anomalies - narrow panel v2.238 CLCN2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN2.
Hereditary ataxia with onset in adulthood v2.86 CLCN2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN2.
Hereditary ataxia with onset in adulthood v2.86 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only. Ataxia is a frequent feature of CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ataxia.
Hereditary ataxia with onset in adulthood v2.86 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.242 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Biallelic' only. Ataxia is a frequent feature of CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ataxia.
Hereditary ataxia v1.242 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.238 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only. Ataxia is a frequent feature of CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ataxia.
Ataxia and cerebellar anomalies - narrow panel v2.238 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.237 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; Leukoencephalopathy with ataxia, 615651 to Leukoencephalopathy with ataxia, OMIM:615651
Inherited white matter disorders v1.141 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Chloride Ion Channel 2(ClC-2) related leukoencephalopathy with intramyelinic oedema; Leukoencephalopathy with ataxia; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukoencephalopathy with ataxia, OMIM:615651
Adult onset leukodystrophy v1.31 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651 to Leukoencephalopathy with ataxia, OMIM:615651
White matter disorders and cerebral calcification - narrow panel v1.206 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Chloride Ion Channel 2(ClC-2) related leukoencephalopathy with intramyelinic oedema to Leukoencephalopathy with ataxia, OMIM:615651
Adult onset hereditary spastic paraplegia v1.73 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, OMIM:270685 to Silver spastic paraplegia syndrome, OMIM:270685; Neuropathy, distal hereditary motor, type VC, OMIM:619112
Childhood onset hereditary spastic paraplegia v2.84 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, OMIM:270685 to Silver spastic paraplegia syndrome, OMIM:270685; Neuropathy, distal hereditary motor, type VC, OMIM:619112
Familial Meniere Disease v1.1 AQP3 Eldar Dedic reviewed gene: AQP3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Monogenic nephrogenic diabetes insipidus v1.8 AVPR2 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: AVPR2.
Renal tubulopathies v2.30 AVPR2 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: AVPR2.
Renal tubulopathies v2.30 AVPR2 Eleanor Williams Phenotypes for gene: AVPR2 were changed from Diabetes insipidus, nephrogenic, 304800; Nephrogenic Diabetes Insipidus; Diabetes Insipidus, Nephrogenic, X-Linked; nephrogenic diabetes insipidus (commonest cause, affected females also reported often with a milder and later presentation); Nephrogenic syndrome of inappropriate antidiuresis, 300539 to Diabetes insipidus, nephrogenic, OMIM:304800; Nephrogenic syndrome of inappropriate antidiuresis, OMIM:300539
Renal tubulopathies v2.29 AVPR2 Eleanor Williams Added comment: Comment on mode of pathogenicity: Gain of function variants
Renal tubulopathies v2.29 AVPR2 Eleanor Williams Mode of pathogenicity for gene: AVPR2 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
Adult onset neurodegenerative disorder v2.197 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, to Silver spastic paraplegia syndrome, OMIM:270685
Hydrocephalus v2.118 MYMK Ivone Leong Tag Q4_21_phenotype tag was added to gene: MYMK.
Hydrocephalus v2.118 MYMK Ivone Leong commented on gene: MYMK
Mosaic skin disorders - deep sequencing v1.5 BRAF Tom Cullup changed review comment from: Note that the primary mosaic phenotypes are melanocytic naevus syndrome (MIM number currently not linked to BRAF) and vascular malformations (no appropriate MIM number currently) - see publications list.
Sources: Expert list; to: Note that the primary mosaic phenotypes are melanocytic naevus syndrome (MIM number currently not linked to BRAF) and vascular malformations (no appropriate MIM number currently) - see publications list.
Sources: Expert list
Fast track form submitted. Note from Prof Kinsler:
We have noticed that BRAF is not included on this panel. As a key player in mosaic diseases of various types this was an error somehow in the preparation of the original list. Without it's inclusion on the panel various conditions cannot be properly tested for. For example 7% of Congenital Melanocytic Naevus syndrome are caused by BRAF mosaicism and approximately 5% of Arteriovenous Malformations.
Hydrocephalus v2.118 MYMK Ivone Leong Tag Q4_21_expert_review tag was added to gene: MYMK.
Mosaic skin disorders - deep sequencing v1.5 BRAF Tom Cullup gene: BRAF was added
gene: BRAF was added to Mosaic skin disorders - deep sequencing. Sources: Expert list
Mode of inheritance for gene: BRAF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRAF were set to PMID: 31111470; 31891627; 29461977
Phenotypes for gene: BRAF were set to Melanocytic naevus syndrome (MIM 137550); Vascular malformations; Noonan syndrome 7 (MIM 613706); LEOPARD syndrome 3 (MIM 613707); Cardio-facio-cutaneous syndrome 1 (MIM 115150)
Penetrance for gene: BRAF were set to Complete
Mode of pathogenicity for gene: BRAF 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: BRAF was set to GREEN
Added comment: Note that the primary mosaic phenotypes are melanocytic naevus syndrome (MIM number currently not linked to BRAF) and vascular malformations (no appropriate MIM number currently) - see publications list.
Sources: Expert list
Hydrocephalus v2.118 TCIRG1 Ivone Leong Tag Q4_21_rating tag was added to gene: TCIRG1.
Hydrocephalus v2.118 TCIRG1 Ivone Leong Publications for gene: TCIRG1 were set to
Hydrocephalus v2.117 TCIRG1 Ivone Leong Classified gene: TCIRG1 as Amber List (moderate evidence)
Hydrocephalus v2.117 TCIRG1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Hydrocephalus v2.117 TCIRG1 Ivone Leong Gene: tcirg1 has been classified as Amber List (Moderate Evidence).
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 CFB Eleanor Williams commented on gene: CFB: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Unexplained young onset end-stage renal disease v1.20 CFB Eleanor Williams commented on gene: CFB: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Unexplained kidney failure in young people v1.97 CFB Eleanor Williams Added comment: Comment on mode of inheritance: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Unexplained kidney failure in young people v1.97 CFB Eleanor Williams Mode of inheritance for gene: CFB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Atypical haemolytic uraemic syndrome v2.10 CFB Eleanor Williams Added comment: Comment on mode of inheritance: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Atypical haemolytic uraemic syndrome v2.10 CFB Eleanor Williams Mode of inheritance for gene: CFB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Clefting v2.57 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Fetal anomalies v1.728 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Skeletal dysplasia v2.137 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184.
Skeletal dysplasia v2.137 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Limb disorders v2.65 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Clefting v2.56 SCUBE3 Sarah Leigh Deleted their comment
Clefting v2.56 SCUBE3 Sarah Leigh edited their review of gene: SCUBE3: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined.; Changed rating: AMBER
Clefting v2.56 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined.
Clefting v2.56 SCUBE3 Sarah Leigh Deleted their comment
Clefting v2.56 SCUBE3 Sarah Leigh Tag Q2_21_rating was removed from gene: SCUBE3.
Clefting v2.56 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined
Fetal anomalies v1.727 SCUBE3 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: SCUBE3.
Fetal anomalies v1.727 SCUBE3 Sarah Leigh Tag Q2_21_rating was removed from gene: SCUBE3.
Fetal anomalies v1.727 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Prenatal growth retardation was evident in 8/11 relevant cases.
Limb disorders v2.64 SCUBE3 Sarah Leigh Tag Q4_21_rating tag was added to gene: SCUBE3.
Limb disorders v2.64 SCUBE3 Sarah Leigh Tag Q2_21_rating was removed from gene: SCUBE3.
Limb disorders v2.64 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Brachydactyly was evident in 12/15 cases examined.
Fetal anomalies v1.727 BMPR1B Arina Puzriakova changed review comment from: Comment on mode of inheritance: Biallelic variants lead to the Demirhan type of acromesomelic dysplasia (MIM# 609441) which is pertinent to this panel. Monoallelic variants cause brachydactyly (MIM# 616849 and MIM# 112600) with dysplasia of only a single or few phalanges which would be difficult to diagnose prenatally. For this reason the MOI should remain as biallelic only on this panel.; to: Comment on mode of inheritance: Biallelic variants lead to the Demirhan type of acromesomelic dysplasia (MIM# 609441) which is pertinent to this panel. Monoallelic variants cause brachydactyly (MIM# 616849 and MIM# 112600) with dysplasia of only a single or few phalanges which would be difficult to diagnose prenatally. For this reason the MOI should remain as biallelic only on this panel.
-----
Confirmed with clinical team that this is the appropriate MOI for this panel.
Intellectual disability v3.1364 ZDHHC15 Ivone Leong Added comment: Comment on phenotypes: Previously associated with ?Mental retardation, X-linked 91, OMIM:300577; however, OMIM has removed this
Intellectual disability v3.1364 ZDHHC15 Ivone Leong Phenotypes for gene: ZDHHC15 were changed from ?Mental retardation, X-linked 91, 300577 to cerebral palsy; intellectual disability; autism spectrum disorder; epilepsy
Intellectual disability v3.1363 ZDHHC15 Ivone Leong Added comment: Comment on publications: New publication added PMID:34345675
Intellectual disability v3.1363 ZDHHC15 Ivone Leong Publications for gene: ZDHHC15 were set to 15915161
Fetal anomalies v1.727 SCUBE3 Sarah Leigh Entity copied from Skeletal dysplasia v2.136
Fetal anomalies v1.727 SCUBE3 Sarah Leigh gene: SCUBE3 was added
gene: SCUBE3 was added to Fetal anomalies. Sources: Expert Review Amber,Other
Q2_21_rating tags were added to gene: SCUBE3.
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Penetrance for gene: SCUBE3 were set to unknown
Clefting v2.56 SCUBE3 Sarah Leigh Entity copied from Skeletal dysplasia v2.136
Clefting v2.56 SCUBE3 Sarah Leigh gene: SCUBE3 was added
gene: SCUBE3 was added to Clefting. Sources: Expert Review Amber,Other
Q2_21_rating tags were added to gene: SCUBE3.
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Penetrance for gene: SCUBE3 were set to unknown
Limb disorders v2.64 SCUBE3 Sarah Leigh Entity copied from Skeletal dysplasia v2.136
Limb disorders v2.64 SCUBE3 Sarah Leigh gene: SCUBE3 was added
gene: SCUBE3 was added to Limb disorders. Sources: Expert Review Amber,Other
Q2_21_rating tags were added to gene: SCUBE3.
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Penetrance for gene: SCUBE3 were set to unknown
Intellectual disability v3.1362 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Intellectual disability v3.1362 RAD51 Arina Puzriakova Added comment: Comment on list classification: Intellectual disability has been reported in 2/3 individuals with RAD51-associated FA (third patient with mild early DD). However, a syndromic presentation prior to this is expected. Potential for VUSs in pure ID cohort, although there is an allied chromosome breakage test. Upgrading from Red to Amber - which also reflects the rating of other FA genes associated with ID.
Intellectual disability v3.1362 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1361 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Mirror movements 2, OMIM:614508 to Fanconi anemia, complementation group R, OMIM:617244
Intellectual disability v3.1360 RAD51 Arina Puzriakova Publications for gene: RAD51 were set to 22305526; 21242494
Intellectual disability v3.1359 RAD51 Arina Puzriakova reviewed gene: RAD51: Rating: AMBER; Mode of pathogenicity: None; Publications: 26681308, 26253028, 30907510; Phenotypes: Fanconi anemia, complementation group R, OMIM:617244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial Meniere Disease v1.1 AQP2 Eldar Dedic reviewed gene: AQP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Haematological malignancies cancer susceptibility v2.21 RAD51 Arina Puzriakova Publications for gene: RAD51 were set to 28297620
Haematological malignancies cancer susceptibility v2.20 RAD51 Arina Puzriakova edited their review of gene: RAD51: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Haematological malignancies for rare disease v1.7 RAD51 Arina Puzriakova Publications for gene: RAD51 were set to 28297620
Haematological malignancies for rare disease v1.6 RAD51 Arina Puzriakova edited their review of gene: RAD51: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Haematological malignancies cancer susceptibility v2.20 RAD51 Arina Puzriakova reviewed gene: RAD51: Rating: AMBER; Mode of pathogenicity: None; Publications: 26681308, 26253028, 30907510; Phenotypes: Fanconi anemia, complementation group R, OMIM:617244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Haematological malignancies for rare disease v1.6 RAD51 Arina Puzriakova reviewed gene: RAD51: Rating: AMBER; Mode of pathogenicity: None; Publications: 26681308, 26253028, 30907510; Phenotypes: Fanconi anemia, complementation group R, OMIM:617244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Confirmed Fanconi anaemia or Bloom syndrome v1.13 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Confirmed Fanconi anaemia or Bloom syndrome v1.13 RAD51 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with relevant phenotype and different de novo variants. Phenotype-gene relationship listed in OMIM (MIM# 617244).
Confirmed Fanconi anaemia or Bloom syndrome v1.13 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.264 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Severe microcephaly v2.264 RAD51 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with relevant phenotype and different de novo variants. Phenotype-gene relationship listed in OMIM (MIM# 617244).
Severe microcephaly v2.264 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.63 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Limb disorders v2.63 RAD51 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with relevant phenotype and different de novo variants. Phenotype-gene relationship listed in OMIM (MIM# 617244).
Limb disorders v2.63 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Confirmed Fanconi anaemia or Bloom syndrome v1.12 RAD51 Arina Puzriakova gene: RAD51 was added
gene: RAD51 was added to Confirmed Fanconi anaemia or Bloom syndrome. Sources: Literature
Q4_21_rating tags were added to gene: RAD51.
Mode of inheritance for gene: RAD51 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51 were set to 26681308; 26253028; 30907510
Phenotypes for gene: RAD51 were set to Fanconi anemia, complementation group R, OMIM:617244
Review for gene: RAD51 was set to GREEN
Added comment: Three unrelated patients have been identified to date (PMIDs: 26681308; 26253028; 30907510) with an atypical FA phonotype involving chromosomal instability without bone marrow failure or malignancies along with private heterozygous variants (c.877G>A; c.391A>C; c.725A>G) in the RAD51 gene. Variants occurred de novo with a dominant negative effect. All three individuals presented with thumb and radial abnormalities, microcephaly, and DD/ID (third patient showed early DD but above average IQ by age 13); and two individuals also had growth retardation (probable in third case but not reported on) and hearing impairment.
Sources: Literature
Severe microcephaly v2.263 RAD51 Arina Puzriakova gene: RAD51 was added
gene: RAD51 was added to Severe microcephaly. Sources: Literature
Q4_21_rating tags were added to gene: RAD51.
Mode of inheritance for gene: RAD51 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51 were set to 26681308; 26253028; 30907510
Phenotypes for gene: RAD51 were set to Fanconi anemia, complementation group R, OMIM:617244
Review for gene: RAD51 was set to GREEN
Added comment: Three unrelated patients have been identified to date (PMIDs: 26681308; 26253028; 30907510) with an atypical FA phonotype involving chromosomal instability without bone marrow failure or malignancies along with private heterozygous variants (c.877G>A; c.391A>C; c.725A>G) in the RAD51 gene. Variants occurred de novo with a dominant negative effect. All three individuals presented with thumb and radial abnormalities, microcephaly, and DD/ID (third patient showed early DD but above average IQ by age 13); and two individuals also had growth retardation (probable in third case but not reported on) and hearing impairment.
Sources: Literature
Limb disorders v2.62 RAD51 Arina Puzriakova gene: RAD51 was added
gene: RAD51 was added to Limb disorders. Sources: Literature
Q4_21_rating tags were added to gene: RAD51.
Mode of inheritance for gene: RAD51 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51 were set to 26681308; 26253028; 30907510
Phenotypes for gene: RAD51 were set to Fanconi anemia, complementation group R, OMIM:617244
Review for gene: RAD51 was set to GREEN
Added comment: Three unrelated patients have been identified to date (PMIDs: 26681308; 26253028; 30907510) with an atypical FA phonotype involving chromosomal instability without bone marrow failure or malignancies along with private heterozygous variants (c.877G>A; c.391A>C; c.725A>G) in the RAD51 gene. Variants occurred de novo with a dominant negative effect. All three individuals presented with thumb and radial abnormalities, microcephaly, and DD/ID (third patient showed early DD but above average IQ by age 13); and two individuals also had growth retardation (probable in third case but not reported on) and hearing impairment.
Sources: Literature
Hereditary spastic paraplegia v1.259 ABHD16A Ivone Leong Classified gene: ABHD16A as Green List (high evidence)
Hereditary spastic paraplegia v1.259 ABHD16A Ivone Leong Gene: abhd16a has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong Tag Q4_21_rating was removed from gene: ABHD16A.
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong Entity copied from Intellectual disability v3.1359
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong gene: ABHD16A was added
gene: ABHD16A was added to Hereditary spastic paraplegia. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: ABHD16A.
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
Childhood onset hereditary spastic paraplegia v2.83 ABHD16A Ivone Leong Entity copied from Intellectual disability v3.1359
Childhood onset hereditary spastic paraplegia v2.83 ABHD16A Ivone Leong gene: ABHD16A was added
gene: ABHD16A was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: ABHD16A.
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
White matter disorders and cerebral calcification - narrow panel v1.205 ABHD16A Ivone Leong Entity copied from Intellectual disability v3.1359
White matter disorders and cerebral calcification - narrow panel v1.205 ABHD16A Ivone Leong gene: ABHD16A was added
gene: ABHD16A was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: ABHD16A.
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
Haematological malignancies cancer susceptibility v2.20 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; MDS; AML; Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group R, OMIM:617244
Haematological malignancies for rare disease v1.6 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; MDS; AML; Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group R, OMIM:617244
Intellectual disability v3.1359 ABHD16A Ivone Leong Tag Q4_21_rating tag was added to gene: ABHD16A.
Intellectual disability v3.1359 ABHD16A Ivone Leong Classified gene: ABHD16A as Amber List (moderate evidence)
Intellectual disability v3.1359 ABHD16A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1359 ABHD16A Ivone Leong Gene: abhd16a has been classified as Amber List (Moderate Evidence).
COVID-19 research v1.80 RAD51 Arina Puzriakova Mode of inheritance for gene: RAD51 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1358 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Mirror movements 2,614508 to Mirror movements 2, OMIM:614508
Arthrogryposis v3.129 ERGIC1 Arina Puzriakova Publications for gene: ERGIC1 were set to 28317099; 34037256
Arthrogryposis v3.128 ERGIC1 Arina Puzriakova Classified gene: ERGIC1 as Amber List (moderate evidence)
Arthrogryposis v3.128 ERGIC1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel update - three unrelated families reported to date with arthrogryposis associated with different variants in this gene (PMID: 28317099; 31230720; 34037256).
Arthrogryposis v3.128 ERGIC1 Arina Puzriakova Gene: ergic1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.127 ERGIC1 Arina Puzriakova Tag watchlist was removed from gene: ERGIC1.
Tag Q3_21_rating tag was added to gene: ERGIC1.
Arthrogryposis v3.127 ERGIC1 Arina Puzriakova reviewed gene: ERGIC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31230720; Phenotypes: Arthrogryposis multiplex congenita 2, neurogenic type, OMIM:208100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting v2.55 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Clefting v2.55 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.726 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Fetal anomalies v1.726 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.136 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Skeletal dysplasia v2.136 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb disorders v2.61 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Limb disorders v2.61 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arthrogryposis v3.127 ERGIC1 Arina Puzriakova Tag watchlist tag was added to gene: ERGIC1.
Fetal anomalies v1.725 BHLHA9 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic single nucleotide variants in this gene are associated with Syndactyly, mesoaxial synostotic, with phalangeal reduction (OMIM:609432). Monoallelic duplications of the whole gene are associated with split hand/foot malformations, but it is not clear if they are inherited in an Mendelian manner (see review on the Limb disorders panel https://panelapp.genomicsengland.co.uk/panels/384/gene/BHLHA9/)

Therefore the recommendation is that the mode of inheritance should be biallelic only for this gene, with region being eventually represented by a separate entity.
Fetal anomalies v1.725 BHLHA9 Eleanor Williams Mode of inheritance for gene: BHLHA9 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1357 DDX23 Ivone Leong Publications for gene: DDX23 were set to 33057194
Monogenic hearing loss v2.199 SARS Ivone Leong Tag watchlist was removed from gene: SARS.
Tag new-gene-name tag was added to gene: SARS.
Monogenic hearing loss v2.199 SARS Ivone Leong Tag new-gene-name was removed from gene: SARS.
Monogenic hearing loss v2.199 SARS Ivone Leong Classified gene: SARS as Red List (low evidence)
Monogenic hearing loss v2.199 SARS Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red as only 1 of the cases had hearing loss.
Monogenic hearing loss v2.199 SARS Ivone Leong Gene: sars has been classified as Red List (Low Evidence).
Monogenic hearing loss v2.198 SARS Ivone Leong Entity copied from Intellectual disability v3.1356
Monogenic hearing loss v2.198 SARS Ivone Leong gene: SARS was added
gene: SARS was added to Hearing loss. Sources: Expert Review Amber,Literature
watchlist, new-gene-name tags were added to gene: SARS.
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Severe microcephaly v2.262 SARS Ivone Leong Entity copied from Intellectual disability v3.1356
Severe microcephaly v2.262 SARS Ivone Leong gene: SARS was added
gene: SARS was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist, new-gene-name tags were added to gene: SARS.
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Early onset or syndromic epilepsy v2.446 SARS Ivone Leong Entity copied from Intellectual disability v3.1356
Early onset or syndromic epilepsy v2.446 SARS Ivone Leong gene: SARS was added
gene: SARS was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
watchlist, new-gene-name tags were added to gene: SARS.
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Intellectual disability v3.1356 SARS Ivone Leong Classified gene: SARS as Amber List (moderate evidence)
Intellectual disability v3.1356 SARS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. As there are only 2 cases there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1356 SARS Ivone Leong Gene: sars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1355 SARS Ivone Leong Tag watchlist tag was added to gene: SARS.
Intellectual disability v3.1355 SARS Ivone Leong commented on gene: SARS
Intellectual disability v3.1355 SARS Ivone Leong Tag new-gene-name tag was added to gene: SARS.
Intellectual disability v3.1355 SARS Ivone Leong Phenotypes for gene: SARS were changed from Intellectual disability to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Fetal anomalies v1.724 BHLHA9 Eleanor Williams Phenotypes for gene: BHLHA9 were changed from ?Camptosynpolydactyly, complex, OMIM:607539; Syndactyly, mesoaxial synostotic, with phalangeal reduction, OMIM:609432SPLIT HAND AND FOOT MALFORMATION; MESOAXIAL SYNOSTOTIC SYNDACTYLY WITH PHALANGEAL REDUCTION, MALIK-PERCIN TYPE to ?Camptosynpolydactyly, complex, OMIM:607539; Syndactyly, mesoaxial synostotic, with phalangeal reduction, OMIM:609432; SPLIT HAND AND FOOT MALFORMATION; MESOAXIAL SYNOSTOTIC SYNDACTYLY WITH PHALANGEAL REDUCTION, MALIK-PERCIN TYPE
Fetal anomalies v1.723 BHLHA9 Eleanor Williams Phenotypes for gene: BHLHA9 were changed from SPLIT HAND AND FOOT MALFORMATION; MESOAXIAL SYNOSTOTIC SYNDACTYLY WITH PHALANGEAL REDUCTION, MALIK-PERCIN TYPE to ?Camptosynpolydactyly, complex, OMIM:607539; Syndactyly, mesoaxial synostotic, with phalangeal reduction, OMIM:609432SPLIT HAND AND FOOT MALFORMATION; MESOAXIAL SYNOSTOTIC SYNDACTYLY WITH PHALANGEAL REDUCTION, MALIK-PERCIN TYPE
Fetal anomalies v1.722 BHLHA9 Eleanor Williams Tag Q4_21_MOI tag was added to gene: BHLHA9.
Arthrogryposis v3.127 ERGIC1 Arina Puzriakova Phenotypes for gene: ERGIC1 were changed from Arthrogryposis multiplex congenita 2, neurogenic type; OMIM # 208100 to Arthrogryposis multiplex congenita 2, neurogenic type, OMIM:208100
Structural eye disease v1.83 BEST1 Eleanor Williams Phenotypes for gene: BEST1 were changed from Retinitis pigmentosa, concentric, 613194; Vitelliform Macular degeneration 2, 153700; Microcornea, rod-cone dystrophy, cataract, and posterior; Eye Disorders; Bestrophinopathy, autosomal recessive, 611809; staphyloma; 193220 to ?Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 2, OMIM:193220; Bestrophinopathy, autosomal recessive , OMIM:611809; Macular dystrophy, vitelliform, 2, OMIM:153700; Retinitis pigmentosa, concentric, OMIM:613194; Retinitis pigmentosa-50, OMIM:613194; Vitreoretinochoroidopathy, OMIM:193220
Severe microcephaly v2.261 ATP6V0C Ivone Leong Entity copied from Intellectual disability v3.1354
Severe microcephaly v2.261 ATP6V0C Ivone Leong gene: ATP6V0C was added
gene: ATP6V0C was added to Severe microcephaly. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: ATP6V0C.
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0C were set to 33190975; 33090716
Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly
Early onset or syndromic epilepsy v2.445 ATP6V0C Ivone Leong Entity copied from Intellectual disability v3.1354
Early onset or syndromic epilepsy v2.445 ATP6V0C Ivone Leong gene: ATP6V0C was added
gene: ATP6V0C was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: ATP6V0C.
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0C were set to 33190975; 33090716
Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly
Structural eye disease v1.82 BEST1 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic for now. However two cases with angle closure glaucoma as part of the phenotype have been reported, so adding the watch list tag.
Structural eye disease v1.82 BEST1 Eleanor Williams Mode of inheritance for gene: BEST1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1354 ATP6V0C Ivone Leong Classified gene: ATP6V0C as Amber List (moderate evidence)
Intellectual disability v3.1354 ATP6V0C Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1354 ATP6V0C Ivone Leong Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.81 BEST1 Eleanor Williams Tag watchlist_moi tag was added to gene: BEST1.
Structural eye disease v1.81 BEST1 Eleanor Williams commented on gene: BEST1
Intellectual disability v3.1353 ATP6V0C Ivone Leong Tag watchlist tag was added to gene: ATP6V0C.
Arthrogryposis v3.126 SLC29A3 Arina Puzriakova Publications for gene: SLC29A3 were set to
Severe microcephaly v2.260 ATP11A Ivone Leong Classified gene: ATP11A as Red List (low evidence)
Severe microcephaly v2.260 ATP11A Ivone Leong Gene: atp11a has been classified as Red List (Low Evidence).
Severe microcephaly v2.259 ATP11A Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently only 1 case and a mouse model which showed neurological deficit phenotypes (including tremors, abnormal gait, hind limb clasping and reduction in brain size. The patient was a 26 yo male born to healthy non-consanguineous Japanese parents. At birth his length was -3.3. SD and OFC was -1.3 SD. Developed epilepsy at 2 weeks followed by global developmental delay and mild hypothyroidism and cataracts.He suffered gradual lost of developmental milestones. At 18 yo, height was -4.6 SD and OFC was -4.0 SD.

As there is currently not enough evidence to support a gene-disease association, this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently only 1 case and a mouse model which showed neurological deficit phenotypes (including tremors, abnormal gait, hind limb clasping and reduction in brain size. The patient was a 26 yo male born to healthy non-consanguineous Japanese parents. At birth his length was -3.3. SD and OFC was -1.3 SD. Developed epilepsy at 2 weeks followed by global developmental delay and mild hypothyroidism and cataracts.He suffered gradual lost of developmental milestones. At 18 yo, height was -4.6 SD and OFC was -4.0 SD.

As the mouse model did not show signs of microcephaly, there is currently not enough evidence to support a gene-disease association, this gene has been given an Red rating.
White matter disorders and cerebral calcification - narrow panel v1.204 ATP11A Ivone Leong Entity copied from Intellectual disability v3.1353
White matter disorders and cerebral calcification - narrow panel v1.204 ATP11A Ivone Leong gene: ATP11A was added
gene: ATP11A was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: ATP11A.
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to 34403372
Phenotypes for gene: ATP11A were set to Neurodevelopmental disorder
Inherited white matter disorders v1.140 ATP11A Ivone Leong Entity copied from Intellectual disability v3.1353
Inherited white matter disorders v1.140 ATP11A Ivone Leong gene: ATP11A was added
gene: ATP11A was added to Inherited white matter disorders. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: ATP11A.
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to 34403372
Phenotypes for gene: ATP11A were set to Neurodevelopmental disorder
Severe microcephaly v2.259 ATP11A Ivone Leong Entity copied from Intellectual disability v3.1353
Severe microcephaly v2.259 ATP11A Ivone Leong gene: ATP11A was added
gene: ATP11A was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: ATP11A.
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to 34403372
Phenotypes for gene: ATP11A were set to Neurodevelopmental disorder
Intellectual disability v3.1353 ATP11A Ivone Leong Tag watchlist tag was added to gene: ATP11A.
Intellectual disability v3.1353 ATP11A Ivone Leong Classified gene: ATP11A as Amber List (moderate evidence)
Intellectual disability v3.1353 ATP11A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently only 1 case and a mouse model which showed neurological deficit phenotypes (including tremors, abnormal gait, hind limb clasping and reduction in brain size. The patient was a 26 yo male born to healthy non-consanguineous Japanese parents. At birth his length was -3.3. SD and OFC was -1.3 SD. Developed epilepsy at 2 weeks followed by global developmental delay and mild hypothyroidism and cataracts.He suffered gradual lost of developmental milestones. At 18 yo, height was -4.6 SD and OFC was -4.0 SD.

As there is currently not enough evidence to support a gene-disease association, this gene has been given an Amber rating.
Intellectual disability v3.1353 ATP11A Ivone Leong Gene: atp11a has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.125 SLC29A3 Arina Puzriakova Tag Q4_21_rating tag was added to gene: SLC29A3.
Arthrogryposis v3.125 SLC29A3 Arina Puzriakova Classified gene: SLC29A3 as Amber List (moderate evidence)
Arthrogryposis v3.125 SLC29A3 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lucy Jackson (NHS). Fixed flexion contractures of the fingers, toes and elbows have been reported in FHC and H-syndrome. Sufficient unrelated cases of joint contractures which can be a presenting feature to rate as Green at the next GMS panel update.
Arthrogryposis v3.125 SLC29A3 Arina Puzriakova Gene: slc29a3 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.219 BEST1 Eleanor Williams changed review comment from: Review of mode of inheritance:
Macular dystrophy, vitelliform, 2 OMIM:153700 - many heterozygous cases reported

OMIM also lists Bestrophinopathy, autosomal recessive OMIM:611809 and Retinitis pigmentosa, concentric and Retinitis pigmentosa-50 OMIM:613194 but with no inheritance pattern listed.

Reports for 11 biallelic cases:

PMID: 18179881 Burgess et al 2008 - report on the analysis of the BEST1 gene in 7 affected individuals from 5 unrelated families of European ethnicity. Clinical electrophysiology of affected individuals showed abnormal full-field ERGs in addition to a severe reduction in the electrooculogram (EOG) light rise analogous to that seen with dominant BEST1 mutations that cause both Best disease and autosomal-dominant vitreoretinochoroidopathy. In all families homozygous or compound het variants in BEST1 were found (6 missense, 1 nonsense). 10 asymptomatic heterozygotes were examined in detail and were found to have a normal retinal examination, ERG responses, and EOG light rise.

PMID: 34327816 - Nowomiejska et al 2021 - in retrospective variant-phenotype analysis they report 6 patients with either homozygous or compound het variants in BEST1, aswell as 24 patients with heterozygous variants.; to: Review of mode of inheritance:
Macular dystrophy, vitelliform, 2 OMIM:153700 - many heterozygous cases reported

OMIM also lists Bestrophinopathy, autosomal recessive OMIM:611809 and Retinitis pigmentosa, concentric and Retinitis pigmentosa-50 OMIM:613194 but with no inheritance pattern listed.

Reports for 11 biallelic cases:

PMID: 18179881 Burgess et al 2008 - report on the analysis of the BEST1 gene in 7 affected individuals from 5 unrelated families of European ethnicity. Clinical electrophysiology of affected individuals showed abnormal full-field ERGs in addition to a severe reduction in the electrooculogram (EOG) light rise analogous to that seen with dominant BEST1 mutations that cause both Best disease and autosomal-dominant vitreoretinochoroidopathy. In all families homozygous or compound het variants in BEST1 were found (6 missense, 1 nonsense). 10 asymptomatic heterozygotes were examined in detail and were found to have a normal retinal examination, ERG responses, and EOG light rise.

PMID: 34327816 - Nowomiejska et al 2021 - in a retrospective variant-phenotype analysis they report 6 patients with either homozygous or compound het variants in BEST1, aswell as 24 patients with heterozygous variants.
Pigmentary skin disorders v1.16 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome/H disease; HISTIOCYTOSIS-LYMPHADENOPATHY PLUS SYNDROME to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782
Monogenic hearing loss v2.197 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome; Hyperpigmentation, Cutaneous, with Hypertrichosis, Hepatosplenomegaly, Heart Anomalies, Hearing Loss, and Hypogonadism to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782; Hyperpigmentation, Cutaneous, with Hypertrichosis, Hepatosplenomegaly, Heart Anomalies, Hearing Loss, and Hypogonadism
Skeletal dysplasia v2.135 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome 602782 to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782
Primary immunodeficiency or monogenic inflammatory bowel disease v2.477 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome 602782; Other autoinflammatory diseases with known genetic defect; Hyperpigmentation hypertrichosis, histiocytosis-lymphadenopathy plus syndrome; Autoinflammatory Disorders to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782; Hyperpigmentation hypertrichosis, histiocytosis-lymphadenopathy plus syndrome; Autoinflammatory Disorders
Hypogonadotropic hypogonadism (GMS) v1.47 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome (OMIM 602782) - H syndrome: characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies and hypogonadism to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782; H syndrome: characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies and hypogonadism
Familial diabetes v1.63 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) syndrome to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782; Pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) syndrome
Arthrogryposis v3.124 SLC29A3 Arina Puzriakova Phenotypes for gene: SLC29A3 were changed from Histiocytosis-lymphadenopathy plus syndrome to Histiocytosis-lymphadenopathy plus syndrome, OMIM:602782
Arthrogryposis v3.123 SLC29A3 Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: SLC29A3.
Rare anaemia v1.29 HSCB Arina Puzriakova Tag watchlist tag was added to gene: HSCB.
Rare anaemia v1.29 HSCB Arina Puzriakova Classified gene: HSCB as Amber List (moderate evidence)
Rare anaemia v1.29 HSCB Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Rating Amber, awaiting further cases - single individual reported to date (PMID:32634119) but with strong functional support, including in vitro and animal studies (zebrafish and mouse)
Rare anaemia v1.29 HSCB Arina Puzriakova Gene: hscb has been classified as Amber List (Moderate Evidence).
Rare anaemia v1.28 HSCB Arina Puzriakova Phenotypes for gene: HSCB were changed from Anaemia, sideroblastic, 5 619523 to ?Anemia, sideroblastic, 5, OMIM:619523
Arthrogryposis v3.123 CHRND Ivone Leong Phenotypes for gene: CHRND were changed from Myasthenic syndrome, congenital, 3A, slow-channel 616321; ?Myasthenic syndrome, congenital, 3C, associated with acetylcholine receptor deficiency 616323; Multiple pterygium syndrome, lethal type 253290; Myasthenic syndrome, congenital, 3B, fast-channel 616322 to Multiple pterygium syndrome, lethal type, OMIM:253290
Familial Meniere Disease v1.1 AQP1 Eldar Dedic reviewed gene: AQP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Intellectual disability v3.1352 SNIP1 Sarah Leigh Classified gene: SNIP1 as Amber List (moderate evidence)
Intellectual disability v3.1352 SNIP1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. A single (founder) variant NM_024700.4:c.1097A>G, p.(Glu366Gly) has been reported in over 30 cases of Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501 in the Amish community (PMIDs: 22279524; 34570759). Cases are homozygous for this variant and unaffected members of the families are heterozygous or wt. Overexpression of the equivalent mouse variant in mouse inner medullary collecting duct cells, resulted in a more aggregated appearance in the nucleus compared to wildtype. The variant protein maybe unstable as Western blots showed reduced levels of the variant protein (PMID: 22279524). Whole transcriptomic analysis of patient blood was performed in PMID: 34570759. This revealed 11 upregulated and 32 downregulated genes, of which 24 had previously been associated with neurological disease.
Intellectual disability v3.1352 SNIP1 Sarah Leigh Gene: snip1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.444 SNIP1 Sarah Leigh edited their review of gene: SNIP1: Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. A single (founder) variant NM_024700.4:c.1097A>G, p.(Glu366Gly) has been reported in over 30 cases of Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501 in the Amish community (PMIDs: 22279524; 34570759). Cases are homozygous for this variant and unaffected members of the families are heterozygous or wt. Overexpression of the equivalent mouse variant in mouse inner medullary collecting duct cells, resulted in a more aggregated appearance in the nucleus compared to wildtype. The variant protein maybe unstable as Western blots showed reduced levels of the variant protein (PMID: 22279524). Whole transcriptomic analysis of patient blood was performed in PMID: 34570759. This revealed 11 upregulated and 32 downregulated genes, of which 24 had previously been associated with neurological disease.; Changed rating: AMBER
Intellectual disability v3.1351 SNIP1 Sarah Leigh Publications for gene: SNIP1 were set to 22279524
Retinal disorders v2.219 BEST1 Eleanor Williams Added comment: Comment on phenotypes: Was Achromatopsia, Cone, and Cone-rod Dystrophy; Best macular atrophy (AD); Bestrophinopathy (AR); Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma (AD); Retinitis pigmentosa, concentric (AD); Retinitis pigmentosa-50 (AD); Vitelliform macular dystrophy, adult-onset (AD); Vitreoretinochoroidopathy (AD); Best macular dystrophy, 153700; Maculopathy, bull's-eye; Vitelliform macular dystrophy, adult-onset, 608161; Bestrophinopathy, 611809; Vitreoretinochoroidopathy, 193220; Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma, 1;Best Vitelliform Macular Dystrophy;Eye Disorders;Retinitis pigmentosa;Retinitis Pigmentosa, Recessive;Best macular dystrophy, 153700;Macular Dystrophy/Degeneration/Stargardt Disease;Macular Dystrophy, Vitelliform; VMD;Macular Dystrophy, Vitelliform, Adult-Onset;Best macular dystrophy
Retinal disorders v2.219 BEST1 Eleanor Williams Phenotypes for gene: BEST1 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Best macular atrophy (AD); Bestrophinopathy (AR); Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma (AD); Retinitis pigmentosa, concentric (AD); Retinitis pigmentosa-50 (AD); Vitelliform macular dystrophy, adult-onset (AD); Vitreoretinochoroidopathy (AD); Best macular dystrophy, 153700; Maculopathy, bull's-eye; Vitelliform macular dystrophy, adult-onset, 608161; Bestrophinopathy, 611809; Vitreoretinochoroidopathy, 193220; Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma, 1; Best Vitelliform Macular Dystrophy; Eye Disorders; Retinitis pigmentosa; Retinitis Pigmentosa, Recessive; Best macular dystrophy, 153700; Macular Dystrophy/Degeneration/Stargardt Disease; Macular Dystrophy, Vitelliform; VMD; Macular Dystrophy, Vitelliform, Adult-Onset; Best macular dystrophy to ?Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 2, OMIM:193220; Bestrophinopathy, autosomal recessive , OMIM:611809; Macular dystrophy, vitelliform, 2, OMIM:153700; Retinitis pigmentosa, concentric, OMIM:613194; Retinitis pigmentosa-50, OMIM:613194; Vitreoretinochoroidopathy, OMIM:193220
Retinal disorders v2.218 BEST1 Eleanor Williams Publications for gene: BEST1 were set to
Retinal disorders v2.217 BEST1 Eleanor Williams Added comment: Comment on mode of inheritance: Review of mode of inheritance in Oct 2021 - there are cases of both biallelic and monoallelic inheritance related to a retinal disorder.
Retinal disorders v2.217 BEST1 Eleanor Williams Mode of inheritance for gene: BEST1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v2.216 BEST1 Eleanor Williams reviewed gene: BEST1: Rating: ; Mode of pathogenicity: None; Publications: 18179881, 34327816; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v2.196 CEACAM16 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving mode of inheritance as monoallelic for now but with recommendation for changing to both mono and biallelic after GMS review. 3 reported cases with homozygous variants.
Monogenic hearing loss v2.196 CEACAM16 Eleanor Williams Mode of inheritance for gene: CEACAM16 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.195 CEACAM16 Eleanor Williams Tag Q4_21_MOI tag was added to gene: CEACAM16.
Monogenic hearing loss v2.195 CEACAM16 Eleanor Williams edited their review of gene: CEACAM16: Added comment: Further heterozygous cases:
PMID: 33040498 - Zhang et al 2020 - a heterozygous missense mutation, c.418A>G/p. Thr140Ala in the CEACAM16 gene, segregating with the deafness in this Chinese family. Abstract only accessed.

Homozygous cases:
PMID: 29703829 - Booth et al 2018 - 2 Iranian families with progressive mild-to-moderate hearing loss reported, in which homozygous splice variants ( c.662-1G>C and c.37G>T) were found in CEACAM16. In both families the variant segregated with the phenotype. Heterozygous carriers had normal hearing. Both variants are absent from gnomAD and ExAC.

PMID: 30514912 - Dias et al 2019 - novel and extremely rare loss-of-function variant c.436 C > T/p.(Arg146Ter) in the CEACAM16 gene segregating with post-lingual progressive autosomal recessive hearing loss in 3 individuals from a Brazilian family. This variant is predicted to significantly reduce the size of the wild type protein.; Changed publications to: 33040498, 29703829, 30514912; Changed phenotypes to: Deafness, autosomal recessive 113, OMIM:618410, deafness, autosomal recessive 113, MONDO:0032732, Deafness, autosomal dominant 4B, OMIM:614614, autosomal dominant nonsyndromic deafness 4B, MONDO:0013823; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Clefting v2.54 GDF11 Eleanor Williams Classified gene: GDF11 as Amber List (moderate evidence)
Clefting v2.54 GDF11 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for green rating following GMS review. 2 cases plus mouse model data.
Clefting v2.54 GDF11 Eleanor Williams Gene: gdf11 has been classified as Amber List (Moderate Evidence).
Clefting v2.53 GDF11 Eleanor Williams Phenotypes for gene: GDF11 were changed from Vertebral hypersegmentation and orofacial anomalies (VHO), OMIM #619122 to Vertebral hypersegmentation and orofacial anomalies (VHO), OMIM:619122
Clefting v2.52 GDF11 Eleanor Williams Publications for gene: GDF11 were set to 31215115; 34113007
Clefting v2.51 GDF11 Eleanor Williams Tag Q4_21_rating tag was added to gene: GDF11.
Clefting v2.51 GDF11 Eleanor Williams reviewed gene: GDF11: Rating: ; Mode of pathogenicity: None; Publications: 3411300, 31215115, 10391213; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1350 SNIP1 Sarah Leigh Tag founder-effect tag was added to gene: SNIP1.
Early onset or syndromic epilepsy v2.444 SNIP1 Sarah Leigh Tag founder-effect tag was added to gene: SNIP1.
Intellectual disability v3.1350 SNIP1 Sarah Leigh Phenotypes for gene: SNIP1 were changed from Psychomotor retardation, epilepsy, and craniofacial dysmorphism, 614501; severe developmental delay to Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501; psychomotor retardation, epilepsy, and craniofacial dysmorphism MONDO:0013787
Early onset or syndromic epilepsy v2.444 SNIP1 Sarah Leigh Phenotypes for gene: SNIP1 were changed from Psychomotor retardation, epilepsy, and craniofacial dysmorphism 614501 to Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501; psychomotor retardation, epilepsy, and craniofacial dysmorphism MONDO:0013787
Early onset or syndromic epilepsy v2.443 SNIP1 Sarah Leigh Publications for gene: SNIP1 were set to 22279524
DDG2P v2.49 TMEM260 Sarah Leigh Tag Q4_21_rating tag was added to gene: TMEM260.
Fetal anomalies v1.722 TMEM260 Sarah Leigh Tag Q4_21_rating tag was added to gene: TMEM260.
Fetal anomalies v1.722 TMEM260 Sarah Leigh edited their review of gene: TMEM260: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least eight variants have been reported in at least six unrelated cases. The variants included: one multi-exon deletion resulting in a frameshift, two smaller frameshifting deletions, two nonsense, one splicing change and two missense changes, one of which was shown by cDNA sequencing to result in skipping of exon 3 (PMID 34612517).; Changed rating: GREEN
DDG2P v2.49 TMEM260 Sarah Leigh edited their review of gene: TMEM260: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least eight variants have been reported in at least six unrelated cases. The variants included: one multi-exon deletion resulting in a frameshift, two smaller frameshifting deletions, two nonsense, one splicing change and two missense changes, one of which was shown by cDNA sequencing to result in skipping of exon 3 (PMID 34612517).; Changed rating: GREEN
DDG2P v2.49 TMEM260 Sarah Leigh Publications for gene: TMEM260 were set to 28318500
DDG2P v2.48 TMEM260 Sarah Leigh Phenotypes for gene: TMEM260 were changed from Neurodevelopmental, Cardiac, and Renal Syndrome to Structural heart defects and renal anomalies syndrome OMIM:617478; Structural heart defects and renal anomalies syndrome MONDO:0044321
DDG2P v2.47 TMEM260 Sarah Leigh Classified gene: TMEM260 as Amber List (moderate evidence)
DDG2P v2.47 TMEM260 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.