Submission Details

The MYO6 gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/4/16. This association was made using case-level data only. At least 7 missense, nonsense and frameshift variants have been reported in humans. Loss-of-function variants cause autosomal dominant progressive hearing loss with variable age of onset (childhood – 30s). Hypomorphic missense variants likely are only hearing loss-causing when in trans with a second variant. A family reported in Brownstein et al. 2014 (24105371) had in-frame exon 10 deletion and dominant, progressive hearing loss, with one homozygote with profound congenital HL. This supports MYO6 as dose-dependent. MYO6 was first associated with this disease in humans as early as 2001 (Melchionda et al.). Association is seen in at least 8 probands in 4 publications (11468689, 25999546, 25227905, 18348273). Variants in this gene segregated with disease in >44 additional family members. Three mouse models exist for MYO6, one of which a heterozygote has mild HL. In summary, MYO6 is definitively associated with autosomal dominant nonsyndromic hearing loss. Based on literature review, semi-dominance is likely, in which biallelic variants cause more severe hearing loss. No distinction in mechanism between AD and AR disease exists for this gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 2/20/18.