NM_000256.3(MYBPC3):c.1483C>T (p.Arg495Trp) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 26, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000543508.19

Allele description [Variation Report for NM_000256.3(MYBPC3):c.1483C>T (p.Arg495Trp)]

NM_000256.3(MYBPC3):c.1483C>T (p.Arg495Trp)

Gene:

MYBPC3:myosin binding protein C3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

NM_000256.3(MYBPC3):c.1483C>T (p.Arg495Trp)

HGVS:

NC_000011.10:g.47342719G>A
NG_007667.1:g.14984C>T
NM_000256.3:c.1483C>TMANE SELECT
NP_000247.2:p.Arg495Trp
LRG_386t1:c.1483C>T
LRG_386:g.14984C>T
LRG_386p1:p.Arg495Trp
NC_000011.9:g.47364270G>A

Protein change:

R495W

Links:

dbSNP: rs397515905

NCBI 1000 Genomes Browser:

rs397515905

Molecular consequence:

NM_000256.3:c.1483C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000198913	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Apr 6, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 19150014, 20433692, 18713777, 22765922, 27532257, 25443708, 24111713, 21415409, 27483260, 28138913, 25741868
SCV000623527	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2025)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 19150014, 22765922, 11499718, 18403758, 19659763, 20019025, 20624503, 22857948, 23396983, 24093860, 27532257, 28492532
SCV001430846	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	no assertion criteria provided	Likely pathogenic (Dec 6, 2019)	germline	research	PubMed (12) [See all records that cite these PMIDs] 20433692, 22765922, 18713777, 19150014, 24111713, 27483260, 25443708, 27532257, 23782526, 28138913, 23283745, 24793961
SCV004834617	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jul 29, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 18713777, 19150014, 20433692, 23283745, 25351510, 27532257, 28356264, 28771489, 31919335, 32492895, 33495597, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	4	not provided	not provided	143475	not provided	clinical testing

Citations

PubMed

In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament.

Harris SP, Lyons RG, Bezold KL.

Circ Res. 2011 Mar 18;108(6):751-64. doi: 10.1161/CIRCRESAHA.110.231670. Review.

PubMed [citation]

PMID:: 21415409
PMCID:: PMC3076008

Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations.

Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman JG, Seidman CE.

J Am Coll Cardiol. 2001 Aug;38(2):315-21.

PubMed [citation]

PMID:: 11499718

See all PubMed Citations (29)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000198913.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The p.Arg495Trp variant in MYBPC3 has been reported in at least 15 individuals with hypertrophic cardiomyopathy (HCM; Rodríguez-García 2010 PMID: 20433692, Coto 2012 PMID: 22765922, Rubattu 2016 PMID: 27483260, Walsh 2017 PMID: 27532257, Restrepo-Cordoba 2017 PMID: 28138913, Kim 2020 PMID: 32492895, Lipari 2020 PMID: 31919335, Sepp 2022 PMID: 35626289, LMM data), including in 1 individual who also had another pathogenic variant in MYBPC3 (Berge 2014 PMID: 24111713). This variant was also been identified by other clinical laboratories in ClinVar (Variation ID: 164114) and has also been identified in 0.001% (1/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Additionally, a variant involving this codon (p.Arg495Gln) have been identified in individuals with HCM and has been classified as pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000623527.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 495 of the MYBPC3 protein (p.Arg495Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 19150014, 22765922, 27532257). ClinVar contains an entry for this variant (Variation ID: 164114). 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. This variant disrupts the p.Arg495 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11499718, 18403758, 19659763, 20019025, 20624503, 22857948, 23396983, 24093860, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV001430846.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (12)

Description

The MYBPC3 Arg495Trp variant has been reported in at least >10 HCM cases (see literature), and was found to segregate in one family (GarcÃa-Castro M, et al., 2009). We have identified this variant in a HCM proband of East Asian descent, with no family history of disease. The variant is present at a low frequency in the Genome Aggregation Database (AF=0.000007; http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. Furthermore different rare variants at this position (Arg495Gln and Arg495Gly) have been reported as pathogenic, suggesting that an amino acid substitution at this site may not be tolerated. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) the variant has been reported in more than 10 HCM probands (PS4_supporting), is rare in the general population (PM2), other amino acid changes at this position have been classified as pathogenic (PM5) and multiple in silico tools predict that this variant is deleterious (PP3), therefore we classify MYBPC3 Arg495Trp as 'likely pathogenic'.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004834617.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (12)

Description

This missense variant is located in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 unrelated individuals affected with hypertrophic cardiomyopathy and in a few asymptomatic relatives (PMID: 18713777, 19150014, 20433692, 23283745, 25351510, 27532257, 28356264, 28771489, 31919335, 32492895, 33495597). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at this codon, p.Arg495Gln and p.Arg495Gly, are known to be pathogenic (ClinVar variation ID: 164113, 42537), indicating that arginine at this position is important for the MYBPC3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		4	not provided	not provided	not provided

Last Updated: May 3, 2025

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