ClinVar

Description

Variant summary: USH2A c.12575G>A (p.Arg4192His) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 280866 control chromosomes in the gnomAD database, including one homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00057 vs 0.011), allowing no conclusion about variant significance. c.12575G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with retinitis pigmentosa or hereditary retinal disorders (Avila-Fernandez_2010, Martin-Merida_2019, Weisschuh_2020, Ganapathi_2022) and this variant co-segregated with the disease (Avila-Fernandez_2010, Martin-Merida_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 15 submitters (evaluation after 2014) cite this variant as uncertain significance (n=5), likely pathogenic (n=2) and pathogenic (n=8). Based on the evidence outlined above, the variant was classified as pathogenic.