ClinVar

Description

Variant summary: USH2A c.838C>T (p.Leu280Phe) results in a non-conservative amino acid change located in the LamG-like jellyroll fold (IPR006558)/Laminin N-terminal domain of the encoded protein sequence. Leucine residue at position 280 is highly conserved among 12 orthologs and has been predicted to be the N2 residue of an alpha helix with the replacement by a Phenylalanine as likely to alter the secondary structure of the Usherin protein (Baux_2007). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250912 control chromosomes. c.838C>T has been reported in the literature as distinct genotypes in at-least two individuals affected with Usher Syndrome (example, Baux_2007, Baux_2014). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing one overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.