ClinVar

Description

Variant summary: USH2A c.10931C>T (p.Thr3644Met) 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 8e-05 in 251242 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (8e-05 vs 0.011), allowing no conclusion about variant significance. c.10931C>T has been reported in the literature in individuals undergoing exome sequencing for suspected inherited causes of retinal disorders (example, Katagiri_2014, Tiwari_2016, Kim_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome with some reporting a VUS outcome. At-least one individual with a phenotype of Retinitis Pigmentosa was reported to have compound heterozygous likely disease causing variants in the EYS gene supporting an alternate disease etiology (example, Tiwari_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.