NM_000256.3(MYBPC3):c.3358C>T (p.Arg1120Cys) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 6, 2023
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:: RCV000547056.12

Allele description [Variation Report for NM_000256.3(MYBPC3):c.3358C>T (p.Arg1120Cys)]

NM_000256.3(MYBPC3):c.3358C>T (p.Arg1120Cys)

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.3358C>T (p.Arg1120Cys)

HGVS:

NC_000011.10:g.47332946G>A
NG_007667.1:g.24757C>T
NM_000256.3:c.3358C>TMANE SELECT
NP_000247.2:p.Arg1120Cys
LRG_386t1:c.3358C>T
LRG_386:g.24757C>T
LRG_386p1:p.Arg1120Cys
NC_000011.9:g.47354497G>A

Protein change:

R1120C

Links:

dbSNP: rs368721523

NCBI 1000 Genomes Browser:

rs368721523

Molecular consequence:

NM_000256.3:c.3358C>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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000623591	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30528150, 31514951, 28492532
SCV000886825	Center for Human Genetics, University of Leuven	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 31, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004836613	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30528150, 31514951, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000623591

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 6, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000886825

Center for Human Genetics, University of Leuven

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 31, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004836613

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 2023)

germline

clinical testing

PubMed (3)
[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	8	not provided	not provided	108544	not provided	clinical testing
not provided	germline	yes	not provided	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

High-degree atrioventricular block revealing hypertrophic cardiomyopathy related to a mutation in MYBPC3 gene.

Kouakam C, Boulé S, Brigadeau F.

Presse Med. 2019 Jan;48(1 Pt 1):68-71. doi: 10.1016/j.lpm.2018.11.012. Epub 2018 Dec 7. No abstract available.

PubMed [citation]

PMID:: 30528150

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000623591.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1120 of the MYBPC3 protein (p.Arg1120Cys). This variant is present in population databases (rs368721523, gnomAD 0.01%). This missense change has been observed in individuals with documented episodes of atrioventricular block (PMID: 30528150, 31514951). ClinVar contains an entry for this variant (Variation ID: 454326). 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.

#	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 Center for Human Genetics, University of Leuven, SCV000886825.1

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

#	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	1	not provided

From All of Us Research Program, National Institutes of Health, SCV004836613.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces arginine with cysteine at codon 1120 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30528150) and in an individual affected with dilated cardiomyopathy (PMID: 31514951). This variant has been identified in 7/241840 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		8	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine