Submissions for variant NM_000256.3(MYBPC3):c.3682C>T (p.Arg1228Cys)

gnomAD frequency: 0.00063  dbSNP: rs201312636

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172557	SCV000054760	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154424	SCV000204092	uncertain significance	not specified	2016-05-18	criteria provided, single submitter	clinical testing	The p.Arg1228Cys variant in MYBPC3 has been identified in 8/3600 individuals of unspecified clinical phenotype from the Framingham and Jackson Heart Studies (Bi ck 2012). It has also been identified in 0.1% (13/9766) of African chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201312636). Additionally, this variant has been identified by our laboratory i n 7 individuals (4 with DCM; 1 with HCM; 1 with early onset severe left ventricu lar dysfunction/ biventricular dilation and 1 with an unspecified complex cardia c phenotype), though it did not segregate with disease in 1 of 3 affected indivi duals from 1 family. This amino acid is not well conserved in evolution which su ggests a change at this amino acid may be tolerated. Collectively, these data su pport that the p.Arg1228Cys variant is less likely disease-causing, though addit ional studies are needed to fully assess its clinical significance.
GeneDx	RCV000172557	SCV000208187	likely benign	not provided	2020-09-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31006259, 29121657, 24503780, 28679633, 27896284, 25351510, 23861362, 22958901, 24447051, 22464770, 25637381, 20474083)
Ambry Genetics	RCV000252868	SCV000318095	likely benign	Cardiovascular phenotype	2020-05-07	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.
Invitae	RCV001079402	SCV000623603	likely benign	Hypertrophic cardiomyopathy	2024-01-30	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625350	SCV000745025	uncertain significance	Hypertrophic cardiomyopathy 4	2015-09-21	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000172557	SCV000842847	uncertain significance	not provided	2018-03-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771800	SCV000904497	likely benign	Cardiomyopathy	2019-12-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000625350	SCV001138285	benign	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001102916	SCV001259616	uncertain significance	MYBPC3-Related Disorders	2019-01-21	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154424	SCV002511453	benign	not specified	2022-04-11	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.3682C>T (p.Arg1228Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 150976 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism. The variant, c.3682C>T, has been reported in the literature in individuals affected with cardiomyopathy, including both dilated- and hypertrophic cardiomyopathy (see e.g. in HGMD), however, in at least one family, lack of co-segregation with the disease phenotype (DCM) was noted (Lakdawala_2012). At least one publication reported experimental evidence evaluating an impact on protein structure, and demonstrated that the variant didn't impact domain stability (Suay-Corredara_2021). Ten submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, without evidence for independent evaluation, and classified the variant as VUS (n=5), likely benign (n=4) / benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224170	SCV003920221	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-03-30	criteria provided, single submitter	clinical testing	MYBPC3 NM_000256.3 exon 33 p.Arg1228Cys (c.3682C>T): This variant has been reported in the literature in several individuals with cardiomyopathy (HCM, DCM, LVNC) (Zimmerman 2010 PMID:20474083, Lakdawala 2012 PMID:22464770, Pugh 2014 PMID:24503780, Paterick 2014 PMID:24447051, Lopes 2015 PMID:25351510). However, this variant failed to segregate with disease in at least one family (Lakdawala 2012 PMID:22464770). This variant is also present in 0.1% (33/24194) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/11-47353755-G-A) and is present in ClinVar (Variation ID:161306). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CSER _CC_NCGL, University of Washington	RCV000148670	SCV000190394	uncertain significance	Primary dilated cardiomyopathy	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000154424	SCV000280266	uncertain significance	not specified	2015-04-08	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Arg1228Cys Given the weak case data, failure to segregate, and presence in general population samples, we consider this a variant of uncertain significance. This variant has not been reported in published literature. In a publication on the Laboratory for Molecular Medicine’s (LMM) experience with sequencing for DCM, this variant is noted in a table of variants for which genotyping probes were added to the chip (Zimmerman et al 2010). The Seidmans reported on the occurrence of this variant in the Jackson Heart Study (Bick et al 2012). They found that individuals with multiple rare MYBPC3 variants (including this variant) had a 14-15% lower left ventricular wall thickness. This is a semi-conservative amino acid change with a positively charged Arginine replaced with a neutral Cysteine. This replacement could affect disulfide bonding in the resulting protein. In silico analysis (PolyPhen2) predicts this amino acid change to be probably damaging to the structure/function of the protein. Arginine is highly conserved at this position across species. In total the variant has been seen in ~7 of 6664 laboratory controls and individuals from publicly available population datasets. It is most frequent in African American samples with 0.25% of such individuals carrying the variant. The variant was reported online in 2 of 4137 Caucasian individuals and 5 of 1933 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of January 7th, 2014). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is listed in dbSNP (rs201312636) with entries for the ESP data and the exome chip designed from the ESP data.
Clinical Genetics, Academic Medical Center	RCV000172557	SCV001921954	uncertain significance	not provided		no assertion criteria provided	clinical testing