ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.10724G>A (p.Cys3575Tyr)

gnomAD frequency: 0.00001  dbSNP: rs111033265
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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 RCV000041677 SCV000065373 likely pathogenic Rare genetic deafness 2011-10-17 criteria provided, single submitter clinical testing The Cys3575Tyr variant in USH2A has been reported in two French Canadian proband s with Usher syndrome type II (Dubois 2005) and has been identified in one proba nd by our laboratory. In all probands, the variant was seen in the compound hete rozygous state with another pathogenic USH2A variant or in the homozygous state. In summary, this variant is likely to be pathogenic.
Blueprint Genetics RCV001073926 SCV001239491 pathogenic Retinal dystrophy 2018-06-29 criteria provided, single submitter clinical testing
Invitae RCV001852854 SCV002283980 pathogenic not provided 2023-12-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 3575 of the USH2A protein (p.Cys3575Tyr). This variant is present in population databases (rs111033265, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of Usher syndrome (PMID: 22135276, 25649381; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48356). 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 with a positive predictive value of 95%. This variant disrupts the p.Cys3575 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002496659 SCV002813859 likely pathogenic Usher syndrome type 2A; Retinitis pigmentosa 39 2022-01-03 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003450738 SCV004182184 likely pathogenic Retinitis pigmentosa 39 2023-11-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003450737 SCV004182185 likely pathogenic Usher syndrome type 2A 2023-11-04 criteria provided, single submitter clinical testing

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