Submissions for variant NM_206933.4(USH2A):c.956G>A (p.Cys319Tyr) (rs121912599)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001004780	SCV001164264	likely pathogenic	Usher syndrome	2019-08-27	reviewed by expert panel	curation	The c.956G>A (p.Cys319Tyr) variant in the USH2A gene in present in 15/34508 (.043% with CI 95%) in Latino alleles in gnomAD. No homozygotes were present in gnomAD (https://gnomad.broadinstitute.org). This frequency is consistent with carrier status in the general population for a recessive condition and meets the Hearing Loss Variant Curation Expert Panel cut off to apply PM2_Supporting. This variant has been detected in at least 3 probands with hearing loss. In 1 proband the variant was observed in the homozygous state, and in 2 probands a pathogenic or suspected-pathogenic variants was observed in trans (PM3_Strong; Laboratory for Molecular Medicine internal data; EGL internal data; PMID: 10729113). 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; Laboratory for Molecular Medicine internal data). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3_Strong, PP1.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000303941	SCV000341015	uncertain significance	not provided	2016-05-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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.
Invitae	RCV000303941	SCV001203292	likely pathogenic	not provided	2020-09-18	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 319 of the USH2A protein (p.Cys319Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs121912599, ExAC 0.09%). This variant has been observed in individual(s) with Usher syndrome (PMID: 10729113, 26969326, Invitae). ClinVar contains an entry for this variant (Variation ID: 2355). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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.
OMIM	RCV000002449	SCV000022607	pathogenic	Usher syndrome, type 2A	2000-04-01	no assertion criteria provided	literature only