Submissions for variant NM_001145809.2(MYH14):c.1382G>A (p.Arg461His)

dbSNP: rs370353590

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037024	SCV000060680	uncertain significance	not specified	2016-12-13	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg461His var iant in MYH14 has been identified by our laboratory in 2 individuals with modera te sensorineural hearing loss, but it did not segregate with hearing loss in an affected family member. This variant has also been identified in 2/7738 East Asi an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs370353590); however its frequency is not high enough to rule o ut a pathogenic role. Computational prediction tools and conservation analyses s uggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical sig nificance of the p.Arg461His variant is uncertain, the nonsegregation event sugg ests that it is more likely to be benign.
GeneDx	RCV001770057	SCV001993626	uncertain significance	not provided	2019-05-07	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001770057	SCV003788141	uncertain significance	not provided	2023-07-04	criteria provided, single submitter	clinical testing	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. 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 not expected to disrupt MYH14 protein function. ClinVar contains an entry for this variant (Variation ID: 44048). This variant has not been reported in the literature in individuals affected with MYH14-related conditions. This variant is present in population databases (rs370353590, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 453 of the MYH14 protein (p.Arg453His).