Submissions for variant NM_001145809.2(MYH14):c.2599C>T (p.Arg867Cys)

dbSNP: rs753356694

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001132286	SCV001291941	uncertain significance	Autosomal dominant nonsyndromic hearing loss 4A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197065	SCV001367700	uncertain significance	Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome	2018-11-22	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375401	SCV001571882	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PM2_Moderate, PP3_Supporting
GeneDx	RCV001559437	SCV001781661	likely benign	not provided	2021-04-06	criteria provided, single submitter	clinical testing
Invitae	RCV001559437	SCV002175933	uncertain significance	not provided	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 826 of the MYH14 protein (p.Arg826Cys). This variant is present in population databases (rs753356694, gnomAD 0.01%). This missense change has been observed in individual(s) with deafness (PMID: 27393652). This variant is also known as c.2599C>T (p.R867C). ClinVar contains an entry for this variant (Variation ID: 893634). 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 MYH14 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.