rs201312636

Variant names:

• chr11-47332204-G-A
• rs201312636
• NM_000256.3:c.3682C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP6

The NM_000256.3(MYBPC3):​c.3682C>T​(p.Arg1228Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:7
• Conservation: PhyloP100: 3.04

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a domain Ig-like C2-type 7 (size 93) in uniprot entity MYPC3_HUMAN there are 32 pathogenic changes around while only 0 benign (100%) in NM_000256.3
• BP6: Variant 11-47332204-G-A is Benign according to our data. Variant chr11-47332204-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161306.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3682C>T	p.Arg1228Cys	missense_variant	Exon 33 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3682C>T	p.Arg1228Cys	missense_variant	Exon 33 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3682C>T	p.Arg1228Cys	missense_variant	Exon 32 of 34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000177 AC: 44 AN: 249234 Hom.: 0 AF XY: 0.000141 AC XY: 19 AN XY: 135220

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000262 AC: 383 AN: 1461522 Hom.: 0 Cov.: 33 AF XY: 0.000254 AC XY: 185 AN XY: 727048

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000270

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74492

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000703

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00129 AC: 5

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000215 AC: 26

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Mar 23, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 23, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31006259, 29121657, 24503780, 28679633, 27896284, 25351510, 23861362, 22958901, 24447051, 22464770, 25637381, 20474083) -

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:2 Benign:1

Apr 11, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

May 18, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Apr 08, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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. -

Hypertrophic cardiomyopathy 4 Uncertain:1 Benign:1

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Primary dilated cardiomyopathy Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

MYBPC3-related disorder Uncertain:1

Jan 21, 2019

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Cardiomyopathy Benign:1

Dec 31, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

May 07, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
CardioboostCm	Benign	0.020
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Uncertain	-0.00040	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.1	D;.;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.014	D;D;D
Vest4		0.97
MVP		0.91
MPC		0.97
ClinPred		0.19	T
GERP RS		5.5
Varity_R		0.57
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201312636; hg19: chr11-47353755;