ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.12525G>T (p.Trp4175Cys)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001062307 SCV001227100 pathogenic not provided 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 4175 of the USH2A protein (p.Trp4175Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Usher syndrome or clinical features of inherited retinal disease (PMID: 19881469, 28559085, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Trp4175 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26352687). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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