ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.4385C>T (p.Thr1462Ile)

dbSNP: rs2034687815
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001806755 SCV002051126 uncertain significance not specified 2021-12-14 criteria provided, single submitter clinical testing Variant summary: USH2A c.4385C>T (p.Thr1462Ile) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250650 control chromosomes (gnomAD). c.4385C>T has been reported in the literature in individuals affected with Usher Syndrome, including one homozygote (Fuster-Garca_2018, Mansard__2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV002542365 SCV003472546 pathogenic not provided 2023-01-20 criteria provided, single submitter clinical testing 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. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1462 of the USH2A protein (p.Thr1462Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Usher syndrome (PMID: 30459346). ClinVar contains an entry for this variant (Variation ID: 1331411). For these reasons, this variant has been classified as Pathogenic.

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