MYO7A p.Val1372Gly

The c.4115T>G variant in MYO7A is a missense variant predicted to cause substitution of valine by glycine at amino acid 1372. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001332 (1/75054 alleles) in the African/African-American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.869, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). At least one patient with this variant displayed congenital sensorineural hearing loss, delayed gross motor development, and rod-cone dystrophy, which is highly specific for Usher syndrome (PP4, PMID: 31836858). This individual was compound heterozygous for the variant and a pathogenic variant published by multiple submitters in ClinVar (c.6025del (p.Ala2009Profs*32)) and confirmed in trans by parental testing (1 PM3 point, PMID: 31836858). A different missense variant in the same codon (c.4114G>A (p.Val1372Met), PMID: 33576163), has been reported in the homozygous state in a patient with hearing loss and retinitis pigmentosa. However, this other variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Hearing loss VCEP (PM5_Supporting). In summary, this variant has been classified as a likely pathogenic variant for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP3, PP4, PM2_Supporting, PM5_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/26/2024).