Submissions for variant NM_016239.4(MYO15A):c.4252G>A (p.Gly1418Arg)

gnomAD frequency: 0.00001  dbSNP: rs753790346

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449688	SCV001652940	likely pathogenic	Rare genetic deafness	2020-09-04	criteria provided, single submitter	clinical testing	The p.Gly1418Arg variant in MYO15A has been previously reported in two individuals with congenital profound hearing loss who were compound heterozygous with a second truncating variant on the remaining allele (Park 2014 PMID: 25373420, Zhang 2019 PMID: 30953472). This variant has been identified in 0.003% (1/30602) of South Asian and in 0.0008% (1/113212) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive allele frequency. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3_Strong, PM2, PP3.
GeneDx	RCV001572126	SCV001796710	likely pathogenic	not provided	2022-03-29	criteria provided, single submitter	clinical testing	Observed multiple times with a second MYO15A variant in a patient referred for genetic testing at GeneDx and in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Zhang et al., 2019); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 25373420, 30953472)
Molecular Diagnosis Center for Deafness	RCV002224976	SCV001984899	pathogenic	Autosomal recessive nonsyndromic hearing loss 3		criteria provided, single submitter	clinical testing
Invitae	RCV001572126	SCV002186122	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1418 of the MYO15A protein (p.Gly1418Arg). This variant is present in population databases (rs753790346, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 25373420, 30953472; 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: 1120059). 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 MYO15A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.