ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633542, 29986705, 33398081, 34795337, 34733312)

The p.Tyr2684His variant in MYO15A has been previously reported in at least 3 individuals with hearing loss, one individual was compound heterozygous for a second likely pathogenic MYO15A, and one individual harbored a rare variant of uncertain significance that was confirmed in trans (Cabanillas 2018, Retterer 2015, Santos Serrao de Castro, 2012, LMM unpublished data). The variant has segregated in an affected sibling (Santos Serrao de Castro, 2012). This variant was identified in 0.07% (8/10344) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Tyr2684His variant is uncertain. ACMG/AMP criteria applied: PM3, PP1, PP3.

Recessive, congenital SNHL

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 2684 of the MYO15A protein (p.Tyr2684His). This variant is present in population databases (rs376351191, gnomAD 0.09%). This missense change has been observed in individual(s) with deafness (PMID: 26633542, 29986705; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 322166). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO15A protein function. For these reasons, this variant has been classified as Pathogenic.

Variant summary: MYO15A c.8050T>C (p.Tyr2684His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249008 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYO15A causing Autosomal Recessive Nonsyndromic Hearing Loss 3, allowing no conclusion about variant significance. c.8050T>C has been reported in the literature in multiple individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss (e.g. Retterer_2016, Cabanillas_2018, Booth_2021, Hirsch_2021, Labcorp (formerly Invitae)). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34733312, 29986705, 33398081, 26633542). ClinVar contains an entry for this variant (Variation ID: 322166). Based on the evidence outlined above, the variant was classified as pathogenic.