ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.6937G>T (p.Gly2313Cys) (rs199840367)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000432643 SCV000525066 likely pathogenic not provided 2018-04-26 criteria provided, single submitter clinical testing The G2313C variant in the USH2A gene has been reported previously in association with nonsyndromic retinitis pigmentosa (Sharon et al., 2015; Bravo-Gil et al., 2016). The G2313C variant has also been reported in an individual with pericentral retinitis pigmentosa, however this individual also harbored two additional variants in the USH2A gene and segregation studies were not performed to confirm the phase of these variants (Comander et al., 2017). The G2313C variant is observed in 26/126,258 (0.0206%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The G2313C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in a nearby residue (C2309R, C2309F) have been reported in the Human Gene Mutation Database in association with USH2A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret G2313C as a likely pathogenic variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000432643 SCV000891881 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing
Invitae RCV000432643 SCV001202175 likely pathogenic not provided 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 2313 of the USH2A protein (p.Gly2313Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs199840367, ExAC 0.02%). This variant has been observed in individual(s) with retinitis pigmentosa and to segregate with disease in a family (PMID: 26261414, 27032803, 28981474, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 384319). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV001074794 SCV001240391 pathogenic Retinal dystrophy 2019-07-03 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV001095706 SCV001251524 likely pathogenic Retinitis pigmentosa 39 criteria provided, single submitter research The USH2A c.6937G>T (p.G2313C) variant has been reported in the compound heterozygous state in individuals with isolated RP (PMID: 26261414; 26306921; 27032803; 28981474).
Sharon lab,Hadassah-Hebrew University Medical Center RCV001003268 SCV001161351 likely pathogenic Retinitis pigmentosa 2019-06-23 no assertion criteria provided research

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