Submissions for variant NM_002471.4(MYH6):c.2946G>A (p.Glu982=)

gnomAD frequency: 0.01048  dbSNP: rs145274612

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037466	SCV000061124	benign	not specified	2012-01-27	criteria provided, single submitter	clinical testing	Glu982Glu in exon 23 of MYH6: This variant is classified as benign based on its high frequency in the general population (dbSNP rs145274612; NHLBI Exome Sequenc ing Project, http://evs.gs.washington.edu/EVS).
Invitae	RCV000234739	SCV000287402	benign	Hypertrophic cardiomyopathy 14	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000244702	SCV000317890	benign	Cardiovascular phenotype	2014-12-18	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.
GeneDx	RCV000037466	SCV000515357	benign	not specified	2016-11-08	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770447	SCV000901890	benign	Cardiomyopathy	2015-11-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037466	SCV000917839	benign	not specified	2018-05-29	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.2946G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.011 in 277200 control chromosomes in the gnomAD database, including 37 homozygotes. The observed variant frequency is approximately 439-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. The variant, c.2946G>A, has been reported in the literature in individuals affected with Cardiomyopathy (Posch_2011). This report does not provide an unequivocal conclusion about the association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001529419	SCV001157077	benign	not provided	2023-11-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001529419	SCV002545159	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MYH6: BP4, BP7, BS1, BS2
Fulgent Genetics, Fulgent Genetics	RCV002477093	SCV002803350	benign	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2022-02-17	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529419	SCV001742849	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037466	SCV001923960	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000037466	SCV001955571	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000037466	SCV001968156	benign	not specified		no assertion criteria provided	clinical testing