MYO7A p.Lys2021Arg

The c.6062A>G (NM_000260.4(MYO7A):c.6062A>G (p.Lys2021Arg)) variant in MYO7A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 2021. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.748, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in at least 4 individuals with Usher Syndrome type 1 (from three families). For one of those individuals, they were compound heterozygous for the variant and a pathogenic/likely pathogenic variant (phase unknown) ((NM_000260.4(MYO7A):c.722G>A (p.Arg241His); 0.5 PM3 points; 21436283). In another family, this variant was found in the homozygous state in a male adolescent, 14 years of age, with bilateral congenital hearing loss and features of night blindness (0.5 PM3 points; Allan, 2014; 1). Due to consanguinity, 2 individuals from the same family were homozygous for the variant (0.25 PM3 points; Allam, 2014; 1) (PM3). At least one patient with this disease displayed sensorineural hearing loss and retinitis pigmentosa, which is highly specific for Usher Syndrome 1 (PMID: 21436283; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_supporting, PP3, PM3, PP4; Version 2; 2022). 1. https://docs.google.com/document/d/17VJ_cidV8dqRQMHTzSVrFa-7PrmJ4trkw2wQsNEPqvk/edit