11-47337729-A-G

Variant names:

• chr11-47337729-A-G
• rs187830361
• NM_000256.3:c.2374T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS1 PP3_Strong PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2374T>C​(p.Trp792Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000448 in 1,563,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W792L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 5.82
• Publications: 17 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 16 ACMG points.

• PS1: Transcript NM_000256.3 (MYBPC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-47337729-A-G is Pathogenic according to our data. Variant chr11-47337729-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 36605.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.2374T>C	p.Trp792Arg	missense_variant	Exon 24 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2374T>C	p.Trp792Arg	missense_variant	Exon 24 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2374T>C	p.Trp792Arg	missense_variant	Exon 23 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2374T>C		non_coding_transcript_exon_variant	Exon 24 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151760 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00 AC: 0 AN: 172018 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1412080 Hom.: 0 Cov.: 33 AF XY: 0.00000287 AC XY: 2 AN XY: 697906

African (AFR) AF: 0.00 AC: 0 AN: 32130

American (AMR) AF: 0.00 AC: 0 AN: 37104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25310

East Asian (EAS) AF: 0.00 AC: 0 AN: 36644

South Asian (SAS) AF: 0.00 AC: 0 AN: 80546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1086342

Other (OTH) AF: 0.00 AC: 0 AN: 58584

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151760 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41284

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67954

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000000666134), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00000857 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Jan 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect resulting in abnormal contractile kinetics and reduced protein stability (Smelter et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 36605); This variant is associated with the following publications: (PMID: 27114410, 34135346, 15519027, 23074333, 23299917, 24793961, 26914223, 29451820, 19808356, 25637381, 27532257, 29540445, 32841044, 31447099, 33782553)

Jun 05, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PS3, PS4

May 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYBPC3 c.2374T>C; p.Trp792Arg variant (rs187830361) is reported in the literature in numerous individuals affected with hypertrophic cardiomyopathy (Bos 2014, Murphy 2014, Pan 2012, Theis 2009, Walsh 2017, Van Driest 2004). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant is reported in ClinVar (Variation ID: 36605), and at least one study reported that this variant was overrepresented in individuals with HCM compared to general population controls (Bos 2014). The tryptophan at codon 792 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.886). Consistent with predictions, functional studies of the variant protein suggest it may lead to instability, as the variant protein occurs at lower levels in cells and exhibits an increased rate of degradation compared to wildtype MYBPC3 (Helms 2020, Smelter 2018). Based on available information, this variant is considered to be pathogenic. References: Bos JM et al. Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. Mayo Clin Proc. 2014 Jun;89(6):727-37. PMID: 24793961 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 Murphy SL et al. Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy. J Cardiovasc Transl Res. 2016 Apr;9(2):153-61. PMID: 26914223 Pan S et al. Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation. Circ Cardiovasc Genet. 2012 Dec;5(6):602-10. PMID: 23074333 Smelter DF et al. The HCM-linked W792R mutation in cardiac myosin-binding protein C reduces C6 FnIII domain stability. Am J Physiol Heart Circ Physiol. 2018 Jun 1;314(6):H1179-H1191. PMID: 29451820 Theis JL et al. Expression patterns of cardiac myofilament proteins: genomic and protein analysis of surgical myectomy tissue from patients with obstructive hypertrophic cardiomyopathy. Circ Heart Fail. 2009 Jul;2(4):325-33. PMID: 19808356 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 Van Driest SL et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004 Nov 2;44(9):1903-10. PMID: 15519027

Dec 07, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

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. p.Trp792Arg in the MYBPC3 gene. Given sufficient case data and lack in the general population, we consider this variant likely disease causing and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has been seen in at least 8 unrelated individuals with HCM (not including this patient). The one published case was reported by Van Driest et al (2004), who identified the variant in 1 of 389 individuals studied with HCM. Segregation data was not reported in this study. The same group later reported this variant in two individuals, though it is unclear if they were related to each or if one of them overlaps with the prior report (Theis et al 2009). There are no other reported missense variants at this codon or within 10 codons of position 792 (Cardiogenomics, Google, Van Driest et al 2004). This is a non conservative amino acid change with a non polar, neutral Tryptophan replaced with a polar, positive Arginine. Tryptophan is conserved at codon 792 across species. In silico analysis (PolyPhen) predicts the amino acid change to be probably damaging to protein structure/function, and Mutation Taster predicts disease-causing. Analysis with a sarcomere-specific PolyPhen tool predicts the variant to be pathogenic. In total, the variant has been seen in 1 of 6,596 published controls, laboratory controls, and publicly available general population samples. It was not seen in 200 ethnically diverse control individuals analyzed by Van Driest et al (2004). GeneDx did not see this variant in 100 Caucasian individuals and 100 African American individuals. The variant was recently reported online in 1 of 4158 European-American individuals and 0 of 2038 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of Oct. 19, 2013). The phenotype of that individual 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. Of note, other HCM-causing variants have been seen at similar frequencies in that dataset. There is no missense variation at codon 792 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of Oct 19, 2015).

Hypertrophic cardiomyopathy Pathogenic:3

Apr 26, 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.Trp792Arg variant in MYBPC3 has been previously identified in at least 19 individuals with HCM and segregated with disease in 1 affected relative (Theis 2009 PMID: 19808356, Pan 2012 PMID: 23074333, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 36605) and have been identified in 0.004% (3/67954) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). Animal models in mice have shown that this variant affects protein function (Smelter 2018 PMID: 29451820) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Trp792Arg variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PS3_Moderate.

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 792 of the MYBPC3 protein (p.Trp792Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertropic cardiomyopathy (PMID: 15519027, 19808356, 23074333, 24793961, 27532257). ClinVar contains an entry for this variant (Variation ID: 36605). An algorithm developed specifically for the MYBPC3 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic.

Sep 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2374T>C (p.Trp792Arg) variant of the MYBPC3 gene replaces tryptophane with arginine at codon 792 of the MYBPC3 protein. This variant has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 19808356, 24793961, 25611685, 27532257). Functional studies in mouse cardiomyocytes have shown that this variant results in reduced protein expression due to destabilized C6 FnIII domain of cMyBP-C (PMID: 29451820). This variant has been identified in 7/1563840 chromosomes in the general population by the Genome Aggregation Database (gnomAD, v4.1.0). Computational prediction suggests that this variant may impact protein structure and function (REVEL score 0.886). Based on these evidence, the c.2374T>C (p.Trp792Arg) variant in the MYBPC3 gene is interpreted as likely pathogenic.

Primary familial hypertrophic cardiomyopathy Pathogenic:3

Sep 21, 2015

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 30, 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.2374T>C (p.Trp792Arg) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 172418 control chromosomes. c.2374T>C has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g., van Driest_2004, Theis_2009, Pan_2012, Ho_2018). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (e.g., Smelter_2018, Helms_2020). Mouse cardiomyocytes harboring the variant protein were found to display reduced cMyBP-C protein levels and contractile kinetics similar to cells lacking endogenous cMyBP-C (Smelter_2018). The variant was also shown to contribute to protein instability (Smelter_2018, Helms_2020). Six ClinVar submitters (evaluation after 2014) have classified the variant as pathogenic (n = 3) or likely pathogenic (n = 3). Based on the evidence outlined above, the variant was classified as pathogenic.

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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

Dec 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Pathogenic:1

Mar 25, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2374T>C (p.W792R) alteration is located in exon 24 (coding exon 24) of the MYBPC3 gene. This alteration results from a T to C substitution at nucleotide position 2374, causing the tryptophan (W) at amino acid position 792 to be replaced by an arginine (R). The MYBPC3 c.2374T>C alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals from hypertrophic cardiomyopathy cohorts (Van Driest, 2004; Theis, 2009; Bos, 2014; Murphy, 2016; Walsh, 2017). This amino acid position is highly conserved in available vertebrate species. One functional study indicated this variant may result in protein destabilization and degradation (Smelter, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

MYBPC3-related disorder Pathogenic:1

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a heterozygous change in multiple individuals with hypertrophic cardiomyopathy (PMID: 15519027, 25637381, 26914223, 27532257). Functional studies in mouse cardiomyocytes have shown that this variant results in reduced protein stability (PMID: 29451820). It is absent from the gnomAD population database and thus is presumed to be rare. The c.2374T>C (p.Trp792Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2374T>C (p.Trp792Arg) variant is classified as Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;T;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.7	H;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-12	D;.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.99
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.98
gMVP		0.96
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs187830361; hg19: chr11-47359280;