ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.1000C>G (p.Arg334Gly)

dbSNP: rs397517963
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000041663 SCV000065359 uncertain significance not specified 2017-03-11 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg334Gly variant in USH2A has been identified by our laboratory in 1 Hispanic individual with hearing loss who did not carry a second variant in the USH2A gene. This va riant was absent from large population studies. Two different disease-causing am ino acid changes at codon 334 (p.Arg334Gln and p.Arg334Trp) have previously been reported in individuals with Usher syndrome (Adato 2000, Ouyang 2004, Baux 2007 , Yan 2016) suggesting that changes at this position may not be tolerated. Addit ionally, computational prediction tools and conservation analysis suggest that t he p.Arg334Gly variant may impact the protein; however this information is not p redictive enough to determine pathogenicity. In summary, while there is some sus picion for a pathogenic role, the clinical significance of the p.Arg334Gly varia nt is uncertain.
Counsyl RCV000670778 SCV000795674 uncertain significance Usher syndrome type 2A; Retinitis pigmentosa 39 2017-11-12 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074760 SCV001240355 likely pathogenic Retinal dystrophy 2019-05-27 criteria provided, single submitter clinical testing
Invitae RCV001362594 SCV001558622 likely pathogenic not provided 2023-08-10 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 48342). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 334 of the USH2A protein (p.Arg334Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 29655801; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. This variant disrupts the p.Arg334 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10909849, 15025721, 17405132, 18452394, 19683999, 28894305). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx RCV001362594 SCV004032052 uncertain significance not provided 2023-02-28 criteria provided, single submitter clinical testing Reported in an individual with hearing loss and light sensitivity in published literature (Austin-Tse et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29655801)
Baylor Genetics RCV003466891 SCV004207715 likely pathogenic Retinitis pigmentosa 39 2023-10-26 criteria provided, single submitter clinical testing

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