Submissions for variant NM_206933.4(USH2A):c.2081G>A (p.Cys694Tyr)

gnomAD frequency: 0.00001  dbSNP: rs137954284

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000504759	SCV001245154	likely pathogenic	Usher syndrome	2023-10-25	reviewed by expert panel	curation	The c.2081G>A in USH2A is a missense variant predicted to cause substitution of cysteine to tyrosine at amino acid 694 (p.Cys694Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.002% (2/113290) in the European (non-Finnish) sub-population which is below the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.92 (PP3). This variant has been detected in at least three probands with Usher syndrome whereby pathogenic or suspected-pathogenic variants were confirmed in trans in two individuals (2.5 PM3_Strong points; PMID:28041643, Invitae Internal Data (SCV001372551.2)). Of the confirmed phase counts, the first harbored the p.Glu767SerfsTer21 variant and second harbored the p.Thr4425Met variant in USH2A (PMID:28041643, Invitae Internal Data). The third individual harbored the p.Cys3267Arg variant but phasing was not confirmed (Invitae Internal Data). At least one proband displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A and Usher syndrome (PP4; PMID: 28041643). Two missense variants, c.2081G>C (p.Cys694Ser) and c.2080T>A (p.Cys694Ser), in the same codon have been classified as likely pathogenic or pathogenic for AR Usher syndrome by two submitters in ClinVar (PM5; ClinVar Variation ID:1217348, 813246). In summary, this variant meets the criteria to be classified as likely pathogenic for AR Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Strong, PP4, PM5. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023).
GeneDx	RCV000480360	SCV000565645	uncertain significance	not provided	2022-07-07	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: 32581362, 20591486, 28041643)
Eurofins Ntd Llc (ga)	RCV000480360	SCV000701718	uncertain significance	not provided	2016-10-14	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074179	SCV001239749	likely pathogenic	Retinal dystrophy	2019-02-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000480360	SCV001372551	pathogenic	not provided	2024-06-15	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 694 of the USH2A protein (p.Cys694Tyr). This variant is present in population databases (rs137954284, gnomAD 0.002%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 20591486, 28041643; Invitae). 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: 418533). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV000504759	SCV003927114	pathogenic	Usher syndrome	2022-12-31	criteria provided, single submitter	research
Baylor Genetics	RCV003463976	SCV004207702	likely pathogenic	Retinitis pigmentosa 39	2024-02-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005018793	SCV005641080	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-05-31	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504759	SCV000598795	likely pathogenic	Usher syndrome	2015-01-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000480360	SCV001924716	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000480360	SCV001952295	uncertain significance	not provided		no assertion criteria provided	clinical testing