11-47337534-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM5PP5_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 Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 3.87

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000256.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47337535-G-A is described in Lovd as [Likely_pathogenic].

PP5

Variant 11-47337534-C-T is Pathogenic according to our data. Variant chr11-47337534-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337534-C-T is described in Lovd as [Pathogenic]. Variant chr11-47337534-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2459G>A	p.Arg820Gln	missense_variant	Exon 25 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.2459G>A	p.Arg820Gln	missense_variant	Exon 25 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.2459G>A	p.Arg820Gln	missense_variant	Exon 24 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.2414-23G>A		intron_variant	Intron 24 of 26	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249220

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135196

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461692

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000405

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:3

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. -

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

- -

Jun 20, 2023

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 suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies in zebrafish have shown a phenotype consistent with hypertrophic cardiomyopathy (PMID: 25281569). This variant has been reported in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12628722, 12951062, 14563344, 16181148, 22112859, 22267749, 24510615, 25351510, 27483260, 27532257, 28087566, 32492895, 32830170, 32841044, 33407484, 33487615, 33495596, 33495597, 33658040, 33673806, 33782553). It has been shown that this variant segregates with disease in 6 affected individuals across 3 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 2 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. -

not provided

Pathogenic:3

Dec 30, 2024

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, 36264615, 33673806, 33407484, 34135346, 33658040, 34542152, 34915024, 32492895, 34400558, 32830170, 22267749, 12628722, 18533079, 37652022) -

Aug 03, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 4

Pathogenic:3

Feb 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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: <0.001%). Predicted Consequence/Location: Intron variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.94 (>=0.2, moderate evidence for spliceogenicity)]. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 33095980, 33946315). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 33095980). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV001023449 /3billion dataset). Therefore, this variant is classified as Likely 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

- -

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

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

- -

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. -

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

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

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

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.66

D;D;D

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.2

M;.;.

PrimateAI

Uncertain

0.67

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

GERP RS

4.6

Varity_R

0.51

gMVP

0.64

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over