ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.9842G>T (p.Cys3281Phe)

gnomAD frequency: 0.00002  dbSNP: rs727504654
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Total submissions: 9
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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 RCV000155917 SCV000205628 uncertain significance not specified 2013-09-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Cys3281Phe variant in USH2A has been previously reported in an individual with clinical fea tures of Usher syndrome, but a second variant in the USH2A gene was not identifi ed (Le Quesne Stabej 2012). This variant was not observed in large population st udies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant c annot be determined with certainty; however, based upon its presence in an affec ted individual and its absence from the general population, we lean towards a mo re likely pathogenic role.
Counsyl RCV000666703 SCV000791045 uncertain significance Usher syndrome type 2A; Retinitis pigmentosa 39 2017-04-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000666703 SCV000894748 uncertain significance Usher syndrome type 2A; Retinitis pigmentosa 39 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074861 SCV001240464 uncertain significance Retinal dystrophy 2019-07-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001227049 SCV001399385 uncertain significance not provided 2022-10-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 3281 of the USH2A protein (p.Cys3281Phe). This variant is present in population databases (rs727504654, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of Usher syndrome (PMID: 22135276, 27208204; Invitae). ClinVar contains an entry for this variant (Variation ID: 179132). 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) performed at Invitae indicates that this missense variant is expected to disrupt USH2A 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.
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376534 SCV001573713 uncertain significance Retinitis pigmentosa 39 2021-04-08 criteria provided, single submitter research The USH2A c.9842G>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Mendelics RCV001273698 SCV002519947 pathogenic Usher syndrome type 2A 2022-05-04 criteria provided, single submitter clinical testing
GeneDx RCV001227049 SCV005201530 uncertain significance not provided 2023-11-28 criteria provided, single submitter clinical testing Reported with additional variants in a patient with Usher syndrome in published literature (PMID: 27145477); 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: 22135276, 30245029, 35266249, 27145477)
Natera, Inc. RCV001273698 SCV001457067 uncertain significance Usher syndrome type 2A 2020-09-16 no assertion criteria provided clinical testing

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