11-47334007-C-T

Variant names:

• chr11-47334007-C-T
• rs727504346
• NM_000256.3:c.2909G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000256.3(MYBPC3):​c.2909G>A​(p.Arg970Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000857 in 1,575,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R970W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:15
• Conservation: PhyloP100: 1.47
• Publications: 7 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2909G>A	p.Arg970Gln	missense_variant	Exon 28 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2909G>A	p.Arg970Gln	missense_variant	Exon 28 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2909G>A	p.Arg970Gln	missense_variant	Exon 27 of 34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000541 AC: 10 AN: 184920 AF XY: 0.0000603

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000641

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000907 AC: 129 AN: 1422926 Hom.: 0 Cov.: 33 AF XY: 0.0000752 AC XY: 53 AN XY: 704410

African (AFR) AF: 0.0000612 AC: 2 AN: 32666

American (AMR) AF: 0.000128 AC: 5 AN: 38970

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25472

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37470

South Asian (SAS) AF: 0.00 AC: 0 AN: 80956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50372

Middle Eastern (MID) AF: 0.000525 AC: 3 AN: 5714

European-Non Finnish (NFE) AF: 0.000102 AC: 111 AN: 1092406

Other (OTH) AF: 0.000102 AC: 6 AN: 58900

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.000196 AC: 3 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000212 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000168 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:8

Feb 19, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg970Gln variant in MYBPC3 has been identified in 1 individual with DCM, 2 individuals with HCM, and 1 individual with LVNC (Walsh 2017, Ko 2018, Takasaki 2018, LMM data). It has also been identified in 0.02% (6/28490) of Latino chromosomes by gnomAD (https://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #177832). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: None. -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 24, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in several individuals with cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 22464770, 24503780, 27532257, 28640247, 30188508, 30847666, 32600061, 35653365, 37652022, 32841044); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 24503780, 22464770, 28640247, 30188508, 32600061, 33782553, 35653365, 30847666, 30297972, 34819141, 27532257, 32841044, 37652022) -

Feb 02, 2018

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Apr 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYBPC3 c.2909G>A; p.Arg970Gln variant (rs727504346) is reported in the literature in several individuals affected with hypertrophic cardiomyopathy, dilated cardiomyopathy, or left ventricular noncompaction, although it was not demonstrated to be disease-causing in these individuals (Helms 2020, Ko 2018, Lakdawala 2012, Takaski 2018, Walsh 2017). This variant is found in the general population with an allele frequency of 0.005% (11/216,302 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.151). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Helms AS et al. Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy. Circ Genom Precis Med. 2020 Oct;13(5):396-405. PMID: 32841044. Ko C et al. Genetic testing impacts the utility of prospective familial screening in hypertrophic cardiomyopathy through identification of a nonfamilial subgroup. Genet Med. 2018 Jan;20(1):69-75. PMID: 28640247. Lakdawala NK et al. Genetic testing for dilated cardiomyopathy in clinical practice. J Card Fail. 2012 Apr;18(4):296-303. PMID: 22464770. Takasaki A et al. Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction. Pediatr Res. 2018 Nov;84(5):733-742. PMID: 30188508. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257. -

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Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy Uncertain:2

Jul 20, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 970 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28640247, 30297972, 32841044, 33782553), in one individual affected with dilated cardiomyopathy (PMID: 22464770, 24503780), and in one individual affected with left ventricular noncompaction cardiomyopathy (PMID: 30188508, 32600061). This variant has been identified in 11/216302 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy Uncertain:2

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 970 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28640247, 30297972, 32841044, 33782553), in an individual affected with dilated cardiomyopathy (PMID: 22464770, 24503780), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 30188508, 32600061). This variant has been identified in 11/216302 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jan 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

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 970 of the MYBPC3 protein (p.Arg970Gln). This variant is present in population databases (rs727504346, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 22464770, 27532257, 28640247, 30188508, 30297972). ClinVar contains an entry for this variant (Variation ID: 177832). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Nov 16, 2020

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYBPC3 c.2909G>A (p.Arg970Gln) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 184920 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (5.4e-05 vs 0.001), allowing no conclusion about variant significance. c.2909G>A has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Lakdawala_2012, Pugh_2014, Walsh_2017, Ko_2018, Ho_2018, Takasaki_2018). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Left ventricular noncompaction Uncertain:1

Jan 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in MYBPC3 is predicted to replace arginine with glutamine at codon 970, p.(Arg970Gln). The arginine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is not located in an annotated domain. There is a small physicochemical difference between arginine and glutamine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.01% (114/1,160,438 alleles) in the European (non-Finnish) population. This variant has been reported in individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction (PMID: 22464770, 27532257, 30847666, 32600061, 32841044). Computational evidence predicts an impact on splicing (SpliceAI) for the nucleotide change, and predicts a benign effect for the missense substitution (REVEL = 0.151). RNA studies have not been conducted to confirm the splicing prediction. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3. -

Cardiovascular phenotype Uncertain:1

Dec 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R970Q variant (also known as c.2909G>A), located in coding exon 28 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2909. The arginine at codon 970 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in individuals with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and left ventricular non-compaction (LVNC), but clinical details were limited (Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Takasaki A et al. Pediatr Res, 2018 11;84:733-742; Ko C et al. Genet Med, 2018 01;20:69-75; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
CardioboostCm	Benign	0.017
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T;T
Eigen	Benign	-0.080
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.
PhyloP100		1.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.15
Sift	Benign	0.63	T;.;T
Sift4G	Benign	0.37	T;T;T
Vest4		0.78
MVP		0.82
MPC		0.81
ClinPred		0.31	T
GERP RS		5.1
Varity_R		0.19
gMVP		0.71
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.54		Position offset: -2

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

Other links and lift over

dbSNP: rs727504346; hg19: chr11-47355558; COSMIC: COSV99919705; COSMIC: COSV99919705;