ClinVar

Description

The c.3407G>A variant in USH2A is a missense variant predicted to cause substitution of serine to asparagine at amino acid 1136. This variant is absent from large population studies (PM2_Supporting, gnomAD v2.1.1). The computational predictor REVEL gives a score of 0.466 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been reported in at least 6 probands with USH2A-related disorders, including four individuals with autosomal recessive Usher syndrome and two individuals with isolated retinopathy. Of these individuals, the variant was confirmed in trans with a pathogenic variant in two individuals, but phase with a second pathogenic variant was unclear in the remaining 4 individuals (PM3_VeryStrong; PMID: 22135276, 25991456, 27957503, 36011334). Of note, the two individuals with isolated retinopathy harbored the pathogenic p.Cys759Phe variant, which is commonly found in individuals with an isolated retinopathy phenotype (SCV001334331.1). At least one patient with this variant was diagnosed with Usher syndrome (PP4). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive USH2A-related disorders including Usher syndrome and isolated retinopathy based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PM3_VeryStrong, PP4. (The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2022)