ClinVar Genomic variation as it relates to human health

The c.401T>A (p.Ile134Asn) is a missense variant in MYO7A predicted to cause a substitution of isoleucine to asparagine at amino acid 134. The filtering allele frequency (the lower threshold of the 95% CI of 60/1179894) of this variant is 0.004019% in the European (non-Finnish) population which meets the threshold (≤0.00007, 0.007%) defined by the ClinGen Hearing Loss Expert Panel for PM2_Supporting for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction tool produced a score of 0.938, which is above the threshold necessary to apply PP3 (PP3). This variant has been detected in 7 probands with Usher syndrome. For 2 of those probands, pathogenic variants (c.19-1G>A and p.Gly214Arg) were observed in trans, and in the other 5 probands, a pathogenic variant was observed with unknown phase (4.5 points, PM3_Very Strong, PMIDs: 25468891, 26969326, 33089500, 37510321, Partners LMM Internal Data ClinVar SCV000059786.6). The variant has been reported to segregate with hearing loss in one affected family member (PP1, Partners LMM Internal Data ClinVar SCV000059786.6). At least one patient with this variant displayed features of sensorineural hearing loss and retinitis pigmentosa, which are consistent for Usher syndrome, a condition highly specific for MYO7A (PP4, Partners LMM Internal Data ClinVar SCV000059786.6). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel (PM3_Very Strong, PM2_Supporting, PP1, PP3, PP4). (ClinGen Hearing Loss VCEP specifications version 2; 9/18/2024).

The MYO7A c.401T>A (p.Ile134Asn) variant is a missense variant which has been reported in two studies in which it has been identified in a compound heterozygous state in two patients with Usher syndrome (Bujakowska et al. 2014; Sloan-Heggen et al. 2016). The p.Ile134Asn variant is reported at a frequency of 0.000062 in the European (non-Finnish) population of the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is a rare variant. The p.Ile134Asn variant is highly conserved through evolution, and in silico tools predict the variant to be damaging for the protein function. Functional studies for the variant were not performed. Based on the limited evidence and application of the ACMG criteria, the p.Ile134Asn variant is classified as a variant of unknown significance for MYO7A-related disorders.

The Ile134Asn variant in MYO7A has been reported in one proband with Usher syndr ome Type I and was absent in 172 control chromosomes (Bharadwaj 2000). We have a lso observed this variant in another patient with Usher syndrome with a pathogen ic variant on the other allele. In addition, this residue is highly conserved ac ross species and computational analyses (biochemical amino acid properties, homo logy, PolyPhen2, SIFT) suggest that the variant may impact the protein. In summa ry, this data suggests this variant is likely pathogenic.

Observed in multiple unrelated patients with Usher syndrome referred for genetic testing at GeneDx and in published literature (Sloan-Heggen et al., 2016; Wafa et al., 2021); 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: 10930322, 10094549, 26969326, 33089500, 26582918)

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 134 of the MYO7A protein (p.Ile134Asn). This variant is present in population databases (rs111033181, gnomAD 0.006%). This missense change has been observed in individuals with Usher syndrome (PMID: 25468891, 26969326; Invitae). ClinVar contains an entry for this variant (Variation ID: 43230). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.