ClinVar

Description

Variant summary: USH2A c.13274C>T (p.Thr4425Met) results in a non-conservative amino acid change located in a Fibronectin type III repeat domain (IPR003961) 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 4.4e-05 in 250930 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum for a pathogenic variant in USH2A causing Usher Syndrome (0.011), allowing no conclusion about variant significance. c.13274C>T has been reported in the literature in multiple compound heterozygous individuals affected with Usher Syndrome and Retinitis Pigmentosa (e.g. van Wijk_2004, Baux_2007, Neverling_2012, van Huet_2015, Bonnet_2016, Toms_2020, Gao_2021, Mansard_2021). These data indicate that the variant is very likely to be associated with disease. In some of these cases, the variant was reported in complex alleles with p.Arg4115Cys (e.g. van Wijk_2004, Bonnet_2016) and/or p.Cys759Phe (e.g. Baux_2007, Mansard_2021). 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: 17405132, 24944099, 27460420, 32188678, 22334370, 26927203, 31998945, 32581362, 25999674, 15015129, 34948090). ClinVar contains an entry for this variant (Variation ID: 438011). Based on the evidence outlined above, the variant was classified as pathogenic.