Submissions for variant NM_000256.3(MYBPC3):c.3413G>A (p.Arg1138His)

gnomAD frequency: 0.00106  dbSNP: rs187705120

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000845563	SCV000208170	benign	not provided	2018-08-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26332594, 22763267, 19150014, 21310275, 12110947, 22765922, 20800588, 29032884, 31006259)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000172893	SCV000223884	likely benign	Hypertrophic cardiomyopathy 1	2015-03-18	criteria provided, single submitter	research	The MYBPC3 Arg1138His variant has been previously reported in both the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.017 (72 of 4168 in the European Finnish population), and at a frequency of 0.002 in the European sub-population of the 1000 genomes project (http://www.1000genomes.org/). We observed this variant in a single proband with typical HCM, presented 27 years and has no clear family history of disease. No other variants were identified. The variant has been reported in the literature (Jääskeläinen P, et al., 2002; García-Castro M, et al., 2009; Golbus JR, et al., 2012). Jääskeläinen et al. (2002) sequenced MYBPC3 in a Finnish HCM population and normal cohort, and identified this Arg1138His variant in multiple families (3 unrelated probands and 5 normal control samples). The variant does not co-segregate with disease and homozygous individuals did not express the HCM phenotype. Another report from Garcia-Castro et al. (2009) identified the Arg1138His variant in a single proband amongst a Spanish HCM population, however this proband is described as having no family history of disease and a concentric pattern of hypertrophy (IVS and PW 19mm). Arginine (Arg) at position 1138 is conserved across distantly related species, however the computational tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), cannot predict the outcome of this MYBPC3 Arg1138His variant. Due to the allele frequency of > 0.001 in population databases, and literature evidence, we classify this variant as "likely benign".
Invitae	RCV000629118	SCV000750032	benign	Hypertrophic cardiomyopathy	2024-01-18	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845563	SCV000987692	likely benign	not provided		criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852647	SCV000995352	likely benign	Cardiomyopathy	2017-12-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000988535	SCV001138287	benign	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000852647	SCV001353191	benign	Cardiomyopathy	2018-11-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453507	SCV002612763	benign	Cardiovascular phenotype	2019-06-01	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	RCV000852647	SCV004239380	likely benign	Cardiomyopathy	2023-01-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154288	SCV000203947	uncertain significance	not specified	2013-02-11	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Blueprint Genetics	RCV000157320	SCV000207055	likely benign	Primary familial hypertrophic cardiomyopathy	2014-03-25	no assertion criteria provided	clinical testing
Blueprint Genetics	RCV000157321	SCV000207056	likely benign	Primary dilated cardiomyopathy	2014-03-25	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000845563	SCV001740288	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000845563	SCV001931387	likely benign	not provided		no assertion criteria provided	clinical testing