MYO7A p.Gly2187Asp

The c.6560G>A variant in MYO7A is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 2187. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001190 (1/84018 alleles) in the European (non-Finnish) 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 0.915, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A (PP3). At least one patient with this variant displayed profound congenital deafness and retinitis pigmentosa, which is highly specific for Usher syndrome (PP4, PMID:10930322). This variant has been detected in at least two individuals with Usher syndrome. Of those individuals, both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant published by multiple submitters in ClinVar (c.2904G>T (p.Glu968Asp) and c.3719G>A (p.R1240Q)) and both of those were presumed in trans (1 PM3 point, PMID:10930322, LMM) (PM3). In summary, this variant was reviewed by the ClinGen Hearing Loss VCEP and classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PP4, PM3 (ClinGen Hearing Loss VCEP specifications version 2; 7/20/2022).