Submissions for variant NM_206933.4(USH2A):c.11713C>T (p.Arg3905Cys)

gnomAD frequency: 0.00004  dbSNP: rs368675850

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001252669	SCV001428428	likely pathogenic	Usher syndrome	2020-06-24	reviewed by expert panel	curation	The c.11713C>T (p.Arg3905Cys) variant in USH2A was present in 0.03281% (1/3048) of South Asian chromosomes in gnomAD v3, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined for autosomal recessive hearing loss by the ClinGen Hearing Loss Expert Panel (PM2_Supporting; gnomad.broadinstitute.org). This variant has been reported in 3 individuals with Usher syndrome and a second pathogenic or likely pathogenic variant identified in USH2A, one of which was confirmed to be in trans with the p.Arg3905Cys variant (PM3_Strong; PMID: 28559085, 27208204, 31877679). At least one of these probands was confirmed to have both hearing loss and retinitis pigmentosa, features highly specific for Usher syndrome (PP4). The REVEL computational prediction tool produced a score of 0.8, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_Strong, PM2_Supporting, PP3, PP4.
GeneDx	RCV000482491	SCV000565651	pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25333064, 24944099, 28559085, 27208204, 34781295, 33576794, 32531858, 31877679)
Counsyl	RCV000675144	SCV000800740	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-03-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000482491	SCV001147667	uncertain significance	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000482491	SCV001222081	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3905 of the USH2A protein (p.Arg3905Cys). This variant is present in population databases (rs368675850, gnomAD 0.005%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 24944099, 25333064, 27208204, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 236537). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000225477	SCV001238874	pathogenic	Retinal dystrophy	2018-11-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001252669	SCV002051247	pathogenic	Usher syndrome	2021-12-18	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.11713C>T (p.Arg3905Cys) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 247752 control chromosomes. c.11713C>T has been reported in the literature as a compound heterozygous genotype in multiple comprehensively genotyped individuals affected with Usher Syndrome (example, Ellingford_2016, Stone_2017, Weisschuh_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (P/LP, n=3; VUS, n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000675144	SCV002790421	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2021-11-05	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137832	SCV003807457	pathogenic	Usher syndrome type 2A	2022-05-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM2 moderated, PM3 strong, PP3 supporting
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324522	SCV004030331	pathogenic	Retinitis pigmentosa	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
PreventionGenetics, part of Exact Sciences	RCV004532830	SCV004119567	likely pathogenic	USH2A-related disorder	2023-06-13	criteria provided, single submitter	clinical testing	The USH2A c.11713C>T variant is predicted to result in the amino acid substitution p.Arg3905Cys. This variant has been reported in the homozygous and compound heterozygous state in patients with retinal disorders or Usher syndrome (Baux. 2014. PubMed ID: 24944099; Krawitz. 2014. PubMed ID: 25333064; Ellingford. 2016. PubMed ID: 27208204; Stone. 2017. PubMed ID: 28559085; Karali. 2019. PubMed ID: 31877679; Colombo. 2021. PubMed ID: 33576794; Colombo. 2021. PubMed ID: 34781295). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-215901725-G-A). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003469118	SCV004208207	pathogenic	Retinitis pigmentosa 39	2024-03-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000482491	SCV004238391	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000225477	SCV000282647	uncertain significance	Retinal dystrophy		no assertion criteria provided	clinical testing