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

Total submissions: 6

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	uncertain significance	not provided	2019-11-04	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 several individuals affected with Usher syndrome (PMID: 10729113, 26969326). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Blueprint Genetics	RCV001074393	SCV001239972	pathogenic	Retinal dystrophy	2019-08-06	criteria provided, single submitter	clinical testing
OMIM	RCV000002449	SCV000022607	pathogenic	Usher syndrome, type 2A	2000-04-01	no assertion criteria provided	literature only