ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.7475C>T (p.Ser2492Leu)

gnomAD frequency: 0.00006  dbSNP: rs483353056
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000373313 SCV000340407 uncertain significance not provided 2016-03-16 criteria provided, single submitter clinical testing
Counsyl RCV000670917 SCV000795833 uncertain significance Usher syndrome type 2A; Retinitis pigmentosa 39 2017-11-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000826074 SCV000967569 uncertain significance not specified 2018-10-23 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ser2492Leu va riant in USH2A has been reported in 1 individual with retinitis pigmentosa who a lso harbored the p.Glu767fs pathogenic variant; however, the phasing of these va riants was not determined (Carss 2017). This variant has also been identified in 0.005% (1/19894) of East Asian chromosomes and 0.003% (4/128566) of European ch romosomes by gnomAD (http://gnomad.broadinstitute.org). Serine (Ser) at position 2492 is poorly conserved across species, with three mammals (rat, naked mole ra t, and Bactrian camel) carrying a leucine (Leu) at this position. In addition, c omputational prediction tools and conservation analysis suggest that this varian t may not impact the protein, though this information is not predictive enough t o rule out pathogenicity. In summary, although the clinical significance of the p.Ser2492Leu variant is uncertain, the lack of conservation suggests it is more likely to be benign. ACMG/AMP Criteria applied: PM2, PM3_Supporting, BP4_Strong.
Blueprint Genetics RCV001073464 SCV001239006 uncertain significance Retinal dystrophy 2019-03-08 criteria provided, single submitter clinical testing
GeneDx RCV000373313 SCV001829138 likely pathogenic not provided 2022-11-21 criteria provided, single submitter clinical testing Not observed at a 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: 28041643, 34426522, 32675063, 35266249)
Labcorp Genetics (formerly Invitae), Labcorp RCV000373313 SCV003280880 uncertain significance not provided 2022-06-10 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2492 of the USH2A protein (p.Ser2492Leu). This variant is present in population databases (rs483353056, gnomAD 0.005%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 28041643). ClinVar contains an entry for this variant (Variation ID: 286836). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV000504866 SCV000598827 uncertain significance Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
Natera, Inc. RCV001274241 SCV001458121 uncertain significance Usher syndrome type 2A 2020-09-16 no assertion criteria provided clinical testing

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