Submissions for variant NM_016239.4(MYO15A):c.5977C>T (p.Arg1993Trp)

gnomAD frequency: 0.00004  dbSNP: rs759663463

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnosis Center for Deafness	RCV001822901	SCV001984925	pathogenic	Autosomal recessive nonsyndromic hearing loss 3		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003718416	SCV004509446	pathogenic	not provided	2024-02-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1993 of the MYO15A protein (p.Arg1993Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with deafness (PMID: 30953472, 31581539, 34974475, 35346193). 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: 1185079). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg1993 amino acid residue in MYO15A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23967202, 25792667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001822901	SCV005417235	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3
Fulgent Genetics, Fulgent Genetics	RCV001822901	SCV005644757	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2024-03-21	criteria provided, single submitter	clinical testing
WangQJ Lab, Chinese People's Liberation Army General Hospital	RCV001822901	SCV001762430	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2021-07-01	no assertion criteria provided	clinical testing