ClinVar

Description

Variant summary: USH2A c.2792G>A (p.Cys931Tyr) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251092 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (8.4e-05 vs 0.011), allowing no conclusion about variant significance. c.2792G>A has been reported in the literature in individuals affected with retinitis pigmentosa without strong evidence of causality (Xu_2014, Wang_2019, Chen_2020, Zhu_2021). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24938718, 31106028, 32893482, 32675063). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.