NM_000256.3(MYBPC3):c.1483C>G (p.Arg495Gly) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 31, 2024
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:: RCV000466543.15

Allele description [Variation Report for NM_000256.3(MYBPC3):c.1483C>G (p.Arg495Gly)]

NM_000256.3(MYBPC3):c.1483C>G (p.Arg495Gly)

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>G (p.Arg495Gly)

Other names:

p.R495G:CGG>GGG

HGVS:

NC_000011.10:g.47342719G>C
NG_007667.1:g.14984C>G
NM_000256.3:c.1483C>GMANE SELECT
NP_000247.2:p.Arg495Gly
LRG_386t1:c.1483C>G
LRG_386:g.14984C>G
LRG_386p1:p.Arg495Gly
NC_000011.9:g.47364270G>C
Q14896:p.Arg495Gly
c.1483C>G

Protein change:

R495G

Links:

UniProtKB: Q14896#VAR_045929; dbSNP: rs397515905

NCBI 1000 Genomes Browser:

rs397515905

Molecular consequence:

NM_000256.3:c.1483C>G - 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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Mus musculus Rho-related BTB domain containing 1 (Rhobtb1), transcript variant 2, mRNA
gi|358001062|ref|NM_001252636.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059051	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Feb 6, 2017)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 9562578, 11499718, 18403758, 19659763, 20019025, 20624503, 25740977, 23396983, 21415409, 22765922, 19150014, 20433692, 22857948, 18713777, 24033266
SCV000546465	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 18403758, 19659763, 20624503, 22574137, 9562578, 19150014, 20433692, 22765922, 23396983, 26671970, 28492532
SCV004834618	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Mar 23, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 18403758, 19659763, 20019025, 20624503, 22267749, 23140321, 25611685, 26455666, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059051

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Feb 6, 2017)

germline

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

SCV000546465

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV004834618

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Mar 23, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing
not provided	germline	not provided	18	7	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life.

Calore C, De Bortoli M, Romualdi C, Lorenzon A, Angelini A, Basso C, Thiene G, Iliceto S, Rampazzo A, Melacini P.

J Med Genet. 2015 May;52(5):338-47. doi: 10.1136/jmedgenet-2014-102923. Epub 2015 Mar 4.

PubMed [citation]

PMID:: 25740977

See all PubMed Citations (23)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059051.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	18	not provided	not provided	clinical testing	PubMed (15)

Description

The p.Arg495Gly variant in MYBPC3 has been identified in 7 individuals with HCM (Morita 2008, Frisso 2009, Millat 2010, Calore 2015, LMM data), including 2 who also carried an additional disease-causing variant, and has also been reported b y other clinical laboratories in ClinVar (Variation ID: 42537). This variant seg regated with disease in 3 affected family members from 2 families (Frisso 2009, LMM data). However, this variant did not segregate with disease in all families (Morita 2008). It has been identified in 1/111690 European chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397515 905). In addition, two different amino acid changes at this position (p.Arg495Tr p and p.Arg495Gln) have been reported in individuals with HCM (Niimura 1998, Mar on 2001, Garcia-Castro 2009, Martin 2009, Rodriguez-Garcia 2010, Brito 2012, Cot o 2012, Lopes 2013), suggesting that changes at this position are not tolerated. However, data suggests that the p.Arg495Gln variant may have reduced penetrance . Computational prediction tools and conservation analysis suggest that this var iant may impact the protein. In summary, although additional studies are require d to fully establish its clinical significance, the p.Arg495Gly variant is likel y pathogenic. ACMG/AMP criteria applied (Richards 2015): PS4_Moderate, PM2, PP1, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		18	not provided	7	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000546465.9

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

Description

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 495 of the MYBPC3 protein (p.Arg495Gly). This variant is present in population databases (rs397515905, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18403758, 19659763, 20624503, 22574137). ClinVar contains an entry for this variant (Variation ID: 42537). 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: 9562578, 19150014, 20433692, 22765922, 23396983, 26671970). 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 All of Us Research Program, National Institutes of Health, SCV004834618.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

This missense variant replaces arginine with glycine at codon 495 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 multiple individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 19659763, 20624503, 22267749, 23140321, 25611685, 26455666; www.cardiodb.org). This variant has also been observed in asymptomatic carriers, suggesting incomplete penetrance (PMID: 20019025). This variant has been identified in 1/249206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense substitutions at this codon, p.Arg495Gln and p.Arg495Trp, are reported to be pathogenic (Clinvar variation ID: 164113 and 164114, respectively), indicating the importance of arginine residue at this position. 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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