MYO7A p.His133Asn

The c.397C>A variant in MYO7A is a missense variant predicted to cause substitution of histidine by asparagine at amino acid 133 (p.His133Asn). The filtering allele frequency in gnomAD v4 is 0.01079% (147/1179888) in the European (non-Finnish) population. (PM2_Supporting, BS1, and BA1 are not met). This variant has been reported as compound heterozygous, phase unknown, with a pathogenic variant in three individuals. One individual had a phenotype of Usher syndrome, one individual had congenital, severe to profound hearing loss, and one individual had inherited retinal disease (PM3, PP4; PMID: 36011334, 26969326, 38219857). Two additional individuals with clinical features of Usher syndrome harbored the variant phase unknown with another variant of uncertain significance (PMID: 37466950, SCV001218757.5). The computational predictor REVEL gives a score of 0.937, which is above the threshold necessary to apply PP3 (PP3). Another missense variant, c.397C>T p.His133Tyr, in the same codon has been classified as pathogenic for Usher syndrome by the ClinGen Hearing Loss VCEP (PM5; ClinVar Variation ID: 43228). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP4, PP3, PM5. (ClinGen Hearing Loss VCEP specifications version 2; 03/12/2025).