ClinVar

Description

Variant summary: USH2A c.4124C>T (p.Ser1375Leu) results in a non-conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250610 control chromosomes (gnomAD). c.4124C>T has been reported in the literature in the heterozygous state in an individual affected with Usher Syndrome and in the compound heterozygous state in at least three individuals affected with retinitis pigmentosa, including two siblings where the variant was confirmed to be in trans with a pathogenic variant (e.g. Zein_2015, Colombo_2018, Gao_2019, Gao_2021, Colombo_2022). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.