Submissions for variant NM_002471.4(MYH6):c.4505G>A (p.Arg1502Gln)

gnomAD frequency: 0.00022  dbSNP: rs199936506

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172022	SCV000050997	uncertain significance	Primary dilated cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037507	SCV000061165	uncertain significance	not specified	2012-04-20	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Arg1502Gln vari ant (MYH6) was reported in two individuals with DCM and was absent from at least 792 control chromosomes (Carniel 2005, Hershberger 2010). One of these individ uals also carried a pathogenic DCM variant as well as a second variant in MYH6 ( Ile275Asn). The variant was present in 0.05% (3/7020) of European American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS/); however, this frequency is too low to confidently rul e out a disease causing role. Computational analyses (biochemical amino acid pro perties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong sup port for or against an impact to the protein. In summary, this variant is more likely to be benign but additional studies are needed to determine this with con fidence.
Invitae	RCV000466575	SCV000546159	likely benign	Hypertrophic cardiomyopathy 14	2023-12-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515370	SCV000611483	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2017-05-23	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623195	SCV000740610	uncertain significance	Primary familial dilated cardiomyopathy	2016-07-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001659959	SCV001872891	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	Reported with the I275N variant in the MYH6 gene in two individuals with DCM; one individual also harbored a pathogenic variant in the TNNT2 gene (Hershberger et al., 2010; Rampersaud et al., 2011), and one individual harbored a third missense variant in the MYH6 gene (Carniel et al., 2005); Also reported in two individuals with HCM (Lopes et al., 2015), one individual with Ebstein's anomaly who also harbored two candidate copy number variants (Sicko et al., 2016), and in one individual from the ClinSeq cohort of individuals who underwent exome sequencing but were not selected for a history of cardiomyopathy, arrhythmia or family history of sudden cardiac death, although additional clinical details were not described (Ng et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23861362, 23299917, 20215591, 22337857, 21483645, 25351510, 27788187, 15998695, 32789579, AlMutairi2020[Publication])
CeGaT Center for Human Genetics Tuebingen	RCV001659959	SCV002545158	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	MYH6: BS1
Ambry Genetics	RCV002336131	SCV002636515	likely benign	Cardiovascular phenotype	2020-05-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Revvity Omics, Revvity	RCV001659959	SCV003815381	uncertain significance	not provided	2019-04-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904918	SCV004725306	likely benign	MYH6-related condition	2020-09-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).