MYO7A p.Leu326Gln

The c.977T>A variant in MYO7A is a missense variant predicted to cause substitution of leucine by glutamine at amino acid 326 (p.Leu326Gln). The highest population filtering allele frequency in gnomAD v4.1 is 0.00002995 (7/91056 alleles) in the South Asian 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 0.991, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 3 individuals with autosomal recessive Usher syndrome. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by family testing (1.5 PM3 points, SCV000199549.4, SCV000589578.6, Laboratory for Molecular Medicine, GeneDx). One individual was homozygous for the variant (0.5 PM3 points, PMID: 18181211) (PM3_Strong). At least one patient with this variant displayed sensorineural hearing loss with retinitis pigmentosa, which is highly specific for autosomal recessive Usher syndrome (PP4, SCV000199549.4, Laboratory for Molecular Medicine). 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_Strong, PM2_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 9/24/2024)