rs727504235

Variant names:

• chr11-47333742-C-T
• rs727504235
• NM_000256.3:c.3005G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000256.3(MYBPC3):​c.3005G>A​(p.Arg1002Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000807 in 1,599,466 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1002W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:10
• Conservation: PhyloP100: 5.79
• Publications: 9 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 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000256.3

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.3005G>A	p.Arg1002Gln	missense	Exon 29 of 35	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.3005G>A	p.Arg1002Gln	missense	Exon 29 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.3005G>A	p.Arg1002Gln	missense	Exon 28 of 34	ENSP00000382193.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152210 Hom.: 0 Cov.: 33

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000551 AC: 13 AN: 235732 AF XY: 0.0000548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000740

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000850 AC: 123 AN: 1447138 Hom.: 0 Cov.: 32 AF XY: 0.0000862 AC XY: 62 AN XY: 718856

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.0000906 AC: 4 AN: 44172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.0000995 AC: 110 AN: 1105602

Other (OTH) AF: 0.000117 AC: 7 AN: 59898

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000591 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Uncertain:2

Mar 01, 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 1002 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 performed for this variant. This variant has been reported in at least four individuals affected with hypertrophic cardiomyopathy (PMID: 11815426, 28790153, 27532257, 32841044, 33495597, 33673806, 33782553; Burns 2019, dissertation, University of Sydney) and in one infant affected with sudden death (PMID: 28807990). This variant has also been identified in 16/267108 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.

Oct 04, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy Uncertain:2

Aug 30, 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 1002 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 performed for this variant. This variant has been reported in at least four individuals affected with hypertrophic cardiomyopathy (PMID: 11815426, 28790153, 27532257, 32841044, 33495597, 33673806, 33782553; Burns 2019, dissertation, University of Sydney) and in one infant affected with sudden death (PMID: 28807990). This variant has also been identified in 16/267108 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 05, 2025

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 1002 of the MYBPC3 protein (p.Arg1002Gln). This variant is present in population databases (rs727504235, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 11815426, 27532257, 28790153, 28807990, 29030401, 33673806, 33782553, 37652022). ClinVar contains an entry for this variant (Variation ID: 177622). 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.

Cardiovascular phenotype Uncertain:2

Aug 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1002Q variant (also known as c.3005G>A), located in coding exon 29 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3005. The arginine at codon 1002 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and sudden unexplained death (SUD) cohorts; however, clinical details are limited (Niimura H et al. Circulation, 2002 Jan;105:446-51; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10; Dewar LJ et al. Circ Cardiovasc Genet, 2017 Aug;10; Ho CY et al. Circ Cardiovasc Genet, 2009 Aug;2:314-21; Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-2600; Cirino AL et al. Circ Cardiovasc Genet, 2017 Oct;10; Walsh R et al. Genet. Med., 2017 02;19:192-203; Oakley CE et al. Cell Res., 2004 Apr;14:95-110). 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 available evidence, the clinical significance of this variant remains unclear.

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Jan 26, 2015

Blueprint Genetics

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

not specified Uncertain:1

Apr 05, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1002Gln variant in MYBPC3 has been reported in 3 individuals with HCM (Niimura 2002, Ho 2009 and LVOD unpublished data). This variant was also identified by our laboratory in 1 individual with DCM and in 1 individual with giant right atrium and arrhythmia (LMM unpublished data). In addition, this variant was identified in 4/62092 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Arginine (Arg) at position 1002 is not conserved in evolutionarily distant species and the change to glutamine (Gln) is present in several birds. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the Arg1002Gln variant is uncertain, the presence of the variant amino acid in multiple bird species suggests that it is more likely to be benign.,The Arg1002Gln variant in MYBPC3 has been reported in 3 individuals with HCM (Niimura 2002, Ho 2009 and LVOD unpublished data). This variant was also identified by our laboratory in 1 individual with DCM and in 1 individual with giant right atrium and arrhythmia (LMM unpublished data). In addition, this variant was identified in 4/62092 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Arginine (Arg) at position 1002 is not conserved in evolutionarily distant species and the change to glutamine (Gln) is present in several birds. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the Arg1002Gln variant is uncertain, the presence of the variant amino acid in multiple bird species suggests that it is more likely to be benign.

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

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Aug 25, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in individuals with HCM and DCM, and in one individual with sudden unexplained death in infancy (Niimura et al., 2002; Ho et al., 2009; Coppini et al., 2014; Burns et al, 2017; Walsh et al., 2017; Cirino et al., 2017; Dewar et al., 2017); 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: 21415409, 15115610, 24503780, 11815426, 20031602, 28790153, 28679633, 29030401, 25524337, 28807990, 27532257, 28986452, 33782553, KrylovaNS2020, 33673806, 35653365)

Hypertrophic cardiomyopathy 4 Uncertain:1

Sep 19, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 (19 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 286 heterozygotes, 2 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated immunoglobulin i-set domain (DECIPHER). (I) 0709 - Another missense variant comparable to the one identified in this case has strong previous evidence for being benign. A comparable variant, p.(Arg1002Trp), has been reported 12 times as likely benign/benign in ClinVar. (SB) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as VUS in heterozygous patients with HCM. There have also been limited reports of this variant classified as VUS in patients with DCM and sudden unexplained death (ClinVar, http://cardiodb.org, PMIDs: 11815426, 28790153, 28807990, 29030401). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
CardioboostCm	Uncertain	0.76
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.029	D
Vest4		0.91
MVP		0.86
MPC		0.89
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.52
gMVP		0.64
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs727504235; hg19: chr11-47355293; COSMIC: COSV57030319; COSMIC: COSV57030319;