Submissions for variant NM_002471.4(MYH6):c.3010G>T (p.Ala1004Ser)

gnomAD frequency: 0.00110  dbSNP: rs143978652

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172563	SCV000051405	likely benign	Primary dilated cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037468	SCV000061126	likely benign	not specified	2015-07-16	criteria provided, single submitter	clinical testing	p.Ala1004Ser in exon 23 of MYH6: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (31/11578) of Latino chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs143978652).
Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute	RCV000201499	SCV000243765	uncertain significance	Hypertrophic cardiomyopathy 14	2024-07-24	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV000037468	SCV000308969	likely benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000244450	SCV000319519	likely benign	Cardiovascular phenotype	2019-03-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000037468	SCV000513789	likely benign	not specified	2017-09-08	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201499	SCV000557899	likely benign	Hypertrophic cardiomyopathy 14	2025-02-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000723680	SCV000884189	likely benign	not provided	2020-05-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770446	SCV000901889	likely benign	Cardiomyopathy	2019-03-22	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852696	SCV000995407	likely benign	Primary dilated cardiomyopathy; Ventricular tachycardia	2019-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037468	SCV001360441	likely benign	not specified	2019-07-29	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.3010G>T (p.Ala1004Ser) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 251486 control chromosomes, predominantly at a frequency of 0.0021 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 84 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 Latino origin. c.3010G>T has been reported in the literature in sequencing studies among individuals affected with Cardiomyopathy (Carniel_2005, Brion_2009, Brion_2012, Hershberger_2010, Posch_2011, Waldmuller_2010-unpublished poster, Merlo_2013). These data indicate that the variant may be associated with disease. At-least one co-occurrence with other pathogenic variant(s) has been reported (MYH7 c.1988G>A, p.R663H), providing supporting evidence for a benign role (Waldmuller_2010, unpublished poster abstract). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000723680	SCV003917313	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	MYH6: BS1
OMIM	RCV000015214	SCV000035471	pathogenic	Dilated cardiomyopathy 1EE	2005-07-05	flagged submission	literature only
Eurofins Ntd Llc (ga)	RCV000723680	SCV000082834	uncertain significance	not provided	2013-06-11	flagged submission	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201499	SCV000256193	uncertain significance	Hypertrophic cardiomyopathy 14		flagged submission	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656144	SCV000678338	likely pathogenic	Wolff-Parkinson-White pattern	2017-07-14	flagged submission	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623034	SCV000740607	uncertain significance	Primary familial hypertrophic cardiomyopathy	2016-06-30	flagged submission	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000723680	SCV001740026	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000723680	SCV001921063	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000723680	SCV001930957	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000723680	SCV001959991	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000723680	SCV001969127	likely benign	not provided		no assertion criteria provided	clinical testing
Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	RCV004765306	SCV005374734	uncertain significance	Hypertrophic cardiomyopathy		no assertion criteria provided	research