ClinVar Genomic variation as it relates to human health

Variant summary: MYO7A c.1846C>T (p.Arg616Trp) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 1552046 control chromosomes (i.e. 464 heterozygotes) in the gnomAD database (v4 dataset). This frequency is not higher than the estimated maximum expected for a pathogenic variant in MYO7A causing Usher Syndrome (0.0061), allowing no conclusion about variant significance. c.1846C>T has been reported in the literature in an individual affected with non-syndromic hearing loss (second variant not specified), and in a homozygous patient affected retinal dystrophy, which belong to the Usher syndrome phenotype spectrum (Sommen_2016, Iancu_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 43160). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

The p.Arg616Trp variant (rs369195493) has been previously identified in cohort of patients with suspected autosomal recessive hearing loss (Sommen 2016); however, no clinically relevant details were provided to independently assess the significance of this observation. This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 43160). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans populations of 0.03% (identified in 21 out of 79,010 chromosomes). The arginine at codon 616 is moderately conserved considering 13 species (Alamut software v2.9), although computational analyses suggest this variant has a significant effect on MYO7A protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.Arg616Trp variant cannot be determined with certainty.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 616 of the MYO7A protein (p.Arg616Trp). This variant is present in population databases (rs369195493, gnomAD 0.03%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 27068579). ClinVar contains an entry for this variant (Variation ID: 43160). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.Arg616Trp variant in MYO7A has been reported in 2 individuals with sensori neural hearing loss and segregated with disease in one relative (Sommen 2016, LM M data). It has been identified in 4/9492 of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs369195493). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical signif icance of the p.Arg616Trp is uncertain.

Observed in an individual with hearing loss in published literature; specific patient information is not available (Sommen et al., 2016); 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: 27068579, 34426522)

The MYO7A c.1846C>T variant is predicted to result in the amino acid substitution p.Arg616Trp. This variant was reported in an individual with non-syndromic hearing loss (Table S1, Sommen. 2016. PubMed ID: 27068579). This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-76883842-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

MYO7A: PP3