Submissions for variant NM_002471.4(MYH6):c.2071G>A (p.Val691Ile)

gnomAD frequency: 0.00284  dbSNP: rs148915045

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151220	SCV000199077	likely benign	not specified	2015-03-23	criteria provided, single submitter	clinical testing	p.Val691Ile in exon 18 of MYH6: This variant is not expected to have clinical si gnificance because it has been identified in 0.9% (92/10402) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs148915045).
GeneDx	RCV000151220	SCV000515776	benign	not specified	2017-01-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457574	SCV000557919	benign	Hypertrophic cardiomyopathy 14	2025-01-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619683	SCV000735996	benign	Cardiovascular phenotype	2018-06-11	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769419	SCV000900812	uncertain significance	Cardiomyopathy	2016-04-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151220	SCV001432120	benign	not specified	2020-08-24	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.2071G>A (p.Val691Ile) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 282834 control chromosomes, predominantly at a frequency of 0.0096 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 384 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function has been reported. One co-occurrence with another pathogenic variant has been internally reported (TTR c.424G>A, p.V142I), providing supporting evidence for a benign role. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x), likely benign (1x) and benign (3x). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001701688	SCV004562151	likely benign	not provided	2023-08-16	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000151220	SCV001925333	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701688	SCV001931554	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000151220	SCV001974596	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544355	SCV004799754	benign	MYH6-related disorder	2019-05-03	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).