Submissions for variant NM_000257.4(MYH7):c.4915G>A (p.Ala1639Thr)

dbSNP: rs864309553

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202758	SCV000257660	uncertain significance	not specified	2015-04-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001185802	SCV001352106	uncertain significance	Cardiomyopathy	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1639 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508721	SCV001715062	uncertain significance	not provided	2020-03-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001508721	SCV003817684	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing
Invitae	RCV003586168	SCV004270917	uncertain significance	Hypertrophic cardiomyopathy	2023-08-10	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. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1639 of the MYH7 protein (p.Ala1639Thr). 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 MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 218434). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30297972). This variant is not present in population databases (gnomAD no frequency).