ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.4126T>C (p.Tyr1376His)

gnomAD frequency: 0.00004  dbSNP: rs374449657
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Total submissions: 2
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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 RCV001195477 SCV001365854 likely benign not specified 2020-01-15 criteria provided, single submitter clinical testing The p.Tyr1376His variant in USH2A is classified as likely benign due to a lack of conservation across species. Over 10 mammals harbor a histidine (His) at this position despite high nearby amino acid conservation. ACMG/AMP Criteria applied: BP4_Strong.
Invitae RCV002559239 SCV003296532 uncertain significance not provided 2021-08-26 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 1376 of the USH2A protein (p.Tyr1376His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs374449657, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. 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 histidine 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.

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