11-47337534-C-T

Variant names:

• chr11-47337534-C-T
• rs2856655
• NM_000256.3:c.2459G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM5 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2459G>A​(p.Arg820Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R820W) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 3.87
• Publications: 29 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000256.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47337535-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195850.
• PP5: Variant 11-47337534-C-T is Pathogenic according to our data. Variant chr11-47337534-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2459G>A	p.Arg820Gln	missense_variant	Exon 25 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2459G>A	p.Arg820Gln	missense_variant	Exon 25 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2459G>A	p.Arg820Gln	missense_variant	Exon 24 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2414-23G>A		intron_variant	Intron 24 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249220 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461692 Hom.: 0 Cov.: 33 AF XY: 0.0000344 AC XY: 25 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111866

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000607 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Pathogenic:3

Aug 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 820 of the fibronectin type 3 domain C6 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional study performed in a zebrafish model has shown that this variant causes a phenotype consistent with hypertrophic cardiomyopathy (PMID: 25281569). This variant has been reported in over 30 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12628722, 14563344, 16181148, 22112859, 22267749, 24510615, 25351510, 27483260, 27532257, 28087566, 32492895, 32830170, 32841044, 33407484, 33487615, 33495596, 33495597, 33658040, 33673806, 33782553, 34542152, 38489124, 38757491). It has been shown that this variant segregates with disease in six affected individuals across three families (PMID: 12628722). This variant has been reported in an individual affected with pediatric hypertrophic cardiomyopathy in compound heterozygous state with a different MYBPC3 variant (PMID: 25281569). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 12628722, 15671604, 31524317). A different variant affecting the same codon, p.Arg820Trp, is considered to be disease-causing (ClinVar variation ID: 195850), suggesting that arginine at this position is important for MYBPC3 protein function. This variant has been identified in 5/249220 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Feb 05, 2018

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

Medical Genome Center, National Cerebral and Cardiovascular Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

NM_000256.3: c.2459G>A is identified in the Japanese general populations in a heterozygous manner (MAF 0.0003), and not all heterozygous carriers suffer cardiomyopathy. The variant seems to be a modifier for hypertrophic cardiomyopathy. -

not provided Pathogenic:3

Oct 29, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 03, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 18761664, 23197398, 16181148, 31524317, 23396983, 26688216, 24510615, 12951062, 15671604, 25281569, 27483260, 27532257, 28420666, 29398688, 20975235, 17263690, 22112859, 19149795, 16115294, 24793961, 18929575, 20800588, 28087566, 25351510, 24621997, 20474083, 28679633, 29907873, 30165862, 31451005, 30847666, 31447099, 31142139, 33487615, 33673806, 33407484, 34135346, 33658040, 34542152, 34915024, 18533079, 22267749, 32492895, 36264615, 37652022, 34400558, 32830170, 38042491, 33782553, 12628722, 40115818, 38757491, 32841044, 38489124, 33495596, Gagliardi2025[CaseReport]) -

Hypertrophic cardiomyopathy 4 Pathogenic:3

Mar 10, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 25281569). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008617 /PMID: 12628722 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12628722, 12951062). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 12628722, 12951062). Different missense changes at the same codon (p.Arg820Pro, p.Arg820Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000180970, VCV000195850 /PMID: 20542340). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hypertrophic cardiomyopathy Pathogenic:3

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 820 of the MYBPC3 protein (p.Arg820Gln). This variant is present in population databases (rs2856655, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12628722, 12951062, 18761664, 18929575, 20542340, 20800588, 22112859, 22267749, 25281569, 27483260, 28087566). It is commonly reported in individuals of Japan ancestry (PMID: 12628722, 12951062, 18761664, 18929575, 20542340, 20800588, 22112859, 22267749, 25281569, 27483260, 28087566). This variant is also known as c.2491G>A. ClinVar contains an entry for this variant (Variation ID: 8617). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 25281569). For these reasons, this variant has been classified as Pathogenic. -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg820Gln variant in MYBPC3 has been reported in 16 individuals with HCM, segregated with disease in 6 affected relatives from 3 families (Konno 2003 PMID: 12628722, Nanni 2003 PMID: 12951062, Alders 2003 PMID: 14563344, Shimizu 2003 PMID: 15671604, Konno 2006 PMID: 16181148, Kapplinger 2014 PMID: 24510615, and Hodatsu 2014 PMID: 25281569, LMM data), and has also been reported in ClinVar (Variation ID 8617). Additionally, it has been identified in 3/111676 of European chromosomes and 1/17248 of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2856655). Animal models (zebrafish) support that this variant causes HCM (Hodatsu et al. 2014 PMID: 25281569). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria Applied: PS4, PM2_Supporting, PS3_Moderate, PP1_Moderate. -

Sep 16, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 820 of the fibronectin type 3 domain C6 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional study performed in a zebrafish model has shown that this variant causes a phenotype consistent with hypertrophic cardiomyopathy (PMID: 25281569). This variant has been reported in over 30 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12628722, 14563344, 16181148, 22112859, 22267749, 24510615, 25351510, 27483260, 27532257, 28087566, 32492895, 32830170, 32841044, 33407484, 33487615, 33495596, 33495597, 33658040, 33673806, 33782553, 34542152, 38489124, 38757491). It has been shown that this variant segregates with disease in six affected individuals across three families (PMID: 12628722). This variant has been reported in an individual affected with pediatric hypertrophic cardiomyopathy in compound heterozygous state with a different MYBPC3 variant (PMID: 25281569). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 12628722, 15671604, 31524317). A different variant affecting the same codon, p.Arg820Trp, is considered to be disease-causing (ClinVar variation ID: 195850), suggesting that arginine at this position is important for MYBPC3 protein function. This variant has been identified in 5/249220 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Primary familial hypertrophic cardiomyopathy Pathogenic:2

Jul 10, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYBPC3 c.2459G>A (p.Arg820Gln) results in a conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249220 control chromosomes (gnomAD). c.2459G>A has been reported in the literature in multiple individuals and several families affected with Hypertrophic Cardiomyopathy, many of East Asian ancestry (e.g. Konno_2003, Hodatsu_2014, Chung_2020). These data indicate that the variant is very likely to be associated with disease. A publication reporting experimental evidence evaluating an impact on protein function in a zebrafish model suggests the variant may result in a more severe cardiac phenotype when together with p.Val762Asp in comparison to p.Val762Asp alone; however, since p.Arg820Gln was not examined alone, this study does not necessarily allow convincing conclusions about the variant effect (Hodatsu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 32380161, 25281569, 12628722). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 01, 2023

Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Jul 15, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R820Q variant (also known as c.2459G>A), located in coding exon 25 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2459. The arginine at codon 820 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM), and has been shown to segregate with disease (Konno T et al. J. Am. Coll. Cardiol., 2003 Mar;41:781-6; Nanni L et al. Biochem. Biophys. Res. Commun., 2003 Sep;309:391-8; Bahrudin U et al. J. Mol. Biol., 2008 Dec;384:896-907; Otsuka H et al. Circ. J., 2012 Nov;76:453-61; Lopes LR et al. Heart, 2015 Feb;101:294-301; Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

MYBPC3-related disorder Pathogenic:1

Mar 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYBPC3 c.2459G>A variant is predicted to result in the amino acid substitution p.Arg820Gln. This variant has been reported in the heterozygous state in individuals with hypertrophic cardiomyopathy and segregated with disease in multiple families (see, for example, Konno et al. 2003. PubMed ID: 12628722; Kim et al. 2020. PubMed ID: 32492895; Supplemental Table 2, Field et al. 2022. PubMed ID: 34400558), although it has been detected in the heterozygous state in asymptomatic carriers as well (Konno et al. 2003. PubMed ID: 12628722; Hayashi et al. 2018. PubMed ID: 29907873). It has also been described in the compound heterozygous state with a second MYBPC3 variant in one individual, who was noted to have substantial left ventricular hypertrophy at age 11 (Hodatsu et al. 2014. PubMed ID: 25281569). In vitro and in vivo experimental studies suggest this variant may affect protein function through impaired protein stability or protein-protein interactions within the sarcomere (Hodatsu et al. 2014. PubMed ID: 25281569; Nadvi et al. 2015. PubMed ID: 26688216; Pearce et al. 2024. PubMed ID: 38042491). Alternative nucleotide changes affecting the same amino acid (p.Arg820Trp, p.Arg820Pro) have been reported in individuals with hypertrophic cardiomyopathy (Ripoll Vera et al 2010. PubMed ID: 20542340; Supplementary Table S2, Sepp et al. 2022. PubMed ID: 35626289 ). This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.2	M;.;.
PhyloP100		3.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D;.;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.0090	D;D;D
Vest4		0.78
MVP		0.81
MPC		0.89
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.51
gMVP		0.64
Mutation Taster		=64/36	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2856655; hg19: chr11-47359085; COSMIC: COSV99920803;