ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.2081G>A (p.Cys694Tyr) (rs137954284)

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Total submissions: 6
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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 2020-01-21 reviewed by expert panel curation The c.2081G>A (p.Cys694Tyr) variant in USH2A is present in 0.0003% (the lower threshold of the 95% CI of 2/113290) European alleles (gnomAD v2.1.1), which is low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2). This variant has been detected in at least 1 patient with Usher syndrome in whom a pathogenic or suspected-pathogenic variant was observed in trans (PM3; VCV000002351.6; PMID: 28041643). The patient displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A (PP4; PMID: 28041643). The REVEL computational prediction analysis tool produced a score of 0.92 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive & Usher syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2, PM3, PP4, PP3).
GeneDx RCV000480360 SCV000565645 likely pathogenic not provided 2014-08-29 criteria provided, single submitter clinical testing The C694Y variant that is likely pathogenic was identified in the USH2A gene. The C694Y missense change in the USH2A gene has been reported as a novel variant in an individual with retinitis pigmentosa and it was absent from 360 controls (Clark et al., 2010). The C694Y variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in an external variant database. The C694Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, the loss of a Cysteine residue may affect disulfide bonds. This substitution occurs at a position that is well conserved across species. According to the Human Gene Mutation Database (HGMD) another missense mutation at a nearby codon (C691Y) has been reported in association with Usher syndrome (Stenson et al., 2009), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant; however, the possibility that it is a benign variant cannot be excluded.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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
Invitae RCV000480360 SCV001372551 uncertain significance not provided 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 694 of the USH2A protein (p.Cys694Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs137954284, ExAC 0.002%). This variant has been observed in individuals affected with retinitis pigmentosa or Usher syndrome (PMID: 28041643, 20591486). ClinVar contains an entry for this variant (Variation ID: 418533). 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.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504759 SCV000598795 likely pathogenic Usher syndrome 2015-01-01 no assertion criteria provided research

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