Submissions for variant NM_000256.3(MYBPC3):c.2686G>A (p.Val896Met)

gnomAD frequency: 0.00601  dbSNP: rs35078470

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000143915	SCV000051564	benign	Primary familial hypertrophic cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035521	SCV000059171	benign	not specified	2015-06-25	criteria provided, single submitter	clinical testing	p.Val896Met in exon 26 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 10% (68/690) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs35078470).
CSER _CC_NCGL, University of Washington	RCV000204363	SCV000212192	likely benign	Hypertrophic cardiomyopathy	2015-03-11	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000035521	SCV000228298	likely benign	not specified	2015-05-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204363	SCV000261462	benign	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000251320	SCV000318931	benign	Cardiovascular phenotype	2016-06-06	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.
Illumina Laboratory Services, Illumina	RCV000602093	SCV000372318	likely benign	Hypertrophic cardiomyopathy 4	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000602093	SCV000743549	likely benign	Hypertrophic cardiomyopathy 4	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000602093	SCV000744836	benign	Hypertrophic cardiomyopathy 4	2015-09-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705647	SCV000885759	benign	not provided	2020-12-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776054	SCV000910681	benign	Cardiomyopathy	2018-03-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035521	SCV000919804	benign	not specified	2018-07-31	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2686G>A (p.Val896Met) results in a conservative amino acid change located in the Fibronectin type III of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0064 in 203838 control chromosomes in the gnomAD database, including 16 homozygotes. The observed variant frequency is more than 6-fold above the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is benign. c.2686G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy. These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported in multiple individuals tested at LCA (MYBPC3 c.2373dupG, p.Trp792fsX41; MYH7 c.428G>A, p.Arg143Gln), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845297	SCV000987329	benign	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001106087	SCV001263120	benign	Left ventricular noncompaction 10	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV001705647	SCV001872136	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27737317, 28798025, 27182706, 26332594, 26914223, 27153395, 25569433, 21310275, 25078086, 25637381, 10521296, 21472310, 12110947, 15010274, 25447171, 23299917, 22763267, 24888384, 24055113)
CeGaT Center for Human Genetics Tuebingen	RCV001705647	SCV002544563	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	MYBPC3: BP4, BS2
Fulgent Genetics, Fulgent Genetics	RCV002496532	SCV002805295	benign	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2022-04-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001705647	SCV005224318	likely benign	not provided		criteria provided, single submitter	not provided
Blueprint Genetics	RCV000143915	SCV000188788	likely benign	Primary familial hypertrophic cardiomyopathy	2014-06-26	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000143915	SCV000190370	likely benign	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000602093	SCV000733037	benign	Hypertrophic cardiomyopathy 4		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035521	SCV001919454	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000035521	SCV001956245	benign	not specified		no assertion criteria provided	clinical testing
Cohesion Phenomics	RCV000204363	SCV003800596	benign	Hypertrophic cardiomyopathy	2022-10-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549425	SCV004739628	likely benign	MYBPC3-related disorder	2020-08-24	no assertion criteria provided	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).