Submissions for variant NM_206933.4(USH2A):c.956G>A (p.Cys319Tyr)

gnomAD frequency: 0.00006  dbSNP: rs121912599

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001004780	SCV001164264	pathogenic	Usher syndrome	2022-08-03	reviewed by expert panel	curation	The c.956G>A variant in USH2A is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 319. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002679 (15/34508 alleles) in the Latino/Admixed American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.524, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. At least one patient was homozygous for this variant and displayed moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa, which is highly specific for Usher syndrome (PP4, PMID:10729113). This variant has been detected in 5 individuals with Usher syndrome. For 5 of those individuals, 4 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by family testing (c.3408T>A (p.Ser1136Arg), c.12067-2A>G, c.5329C>T (p.Arg1777Trp), c.15089C>A (p.S5030X)), (4 PM3 points, PMID: 26969326, 33089500, LMM internal data, EGL internal data). One individual was homozygous for the variant (0.5 PM3 points, PMID:10729113) (PM3_VeryStrong). One of the individuals who was compound heterozygous for the variant and another pathogenic variant in USH2A (RCV000599950.1), had an affected sibling in whom both variants segregated (PP1). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP4, PM3_VS, PP1 (Hearing Loss VCEP specifications version 2; 6/15/2022).
Eurofins Ntd Llc (ga)	RCV000303941	SCV000341015	uncertain significance	not provided	2016-05-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824798	SCV000710854	likely pathogenic	Rare genetic deafness	2017-11-01	criteria provided, single submitter	clinical testing	The p.Cys319Tyr variant in USH2A has been reported in 2 individuals with Usher s yndrome (Weston 2000, Sloan-Heggen 2016), and one infant with mild to moderate h earing loss and segregated in an affected sibling (LMM data). One of these indiv iduals was homozygous, and two were compound heterozygous with a second likely p athogenic USH2A variant. This variant has been identified in 0.04% (15/33496) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org/; dbSNP rs121912599) and has also been reported in ClinVar (Var iation ID: 2355). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . Computational prediction tools and conservation analyses suggest that this va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity on its own. In summary, although additional studies ar e required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP criteria applied: PM2, PM5, PP3, PM3_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000303941	SCV001203292	pathogenic	not provided	2024-01-29	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 319 of the USH2A protein (p.Cys319Tyr). This variant is present in population databases (rs121912599, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Usher syndrome and/or inherited retinal dystrophy (PMID: 10729113, 26969326; 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: 2355). 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.
Blueprint Genetics	RCV001074393	SCV001239972	pathogenic	Retinal dystrophy	2019-08-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001004780	SCV001821387	likely pathogenic	Usher syndrome	2021-08-24	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.956G>A (p.Cys319Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250870 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (6e-05 vs 0.011), allowing no conclusion about variant significance. c.956G>A has been reported in the literature in individuals affected with Usher Syndrome or hearing loss (Weston_2000, Cremers_2007, Sloan-Heggen_2016, Wafa_2021). These data indicate that the variant is 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 (pathogenic n=1, likely pathogenic n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV000002449	SCV002060125	likely pathogenic	Usher syndrome type 2A	2021-11-08	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.956G>A(C319Y) is a missense variant classified as likely pathogenic in the context of USH2A-related disorders. C319Y has been observed in cases with relevant disease (PMID: 10729113, 26969326, 33089500). Functional assessments of this variant are not available in the literature. C319Y has been observed in population frequency databases (gnomAD: AMR 0.04%). In summary, NM_206933.2(USH2A):c.956G>A(C319Y) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV003460406	SCV004208366	likely pathogenic	Retinitis pigmentosa 39	2024-03-20	criteria provided, single submitter	clinical testing
OMIM	RCV000002449	SCV000022607	pathogenic	Usher syndrome type 2A	2000-04-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000002449	SCV002094004	likely pathogenic	Usher syndrome type 2A	2020-01-30	no assertion criteria provided	clinical testing