NM_000256.3(MYBPC3):c.1112C>G (p.Pro371Arg) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 8, 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:: RCV000547807.10

Allele description [Variation Report for NM_000256.3(MYBPC3):c.1112C>G (p.Pro371Arg)]

NM_000256.3(MYBPC3):c.1112C>G (p.Pro371Arg)

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.1112C>G (p.Pro371Arg)

HGVS:

NC_000011.10:g.47343603G>C
NG_007667.1:g.14100C>G
NM_000256.3:c.1112C>GMANE SELECT
NP_000247.2:p.Pro371Arg
LRG_386t1:c.1112C>G
LRG_386:g.14100C>G
LRG_386p1:p.Pro371Arg
NC_000011.9:g.47365154G>C
c.1112C>G

Protein change:

P371R

Links:

dbSNP: rs397515887

NCBI 1000 Genomes Browser:

rs397515887

Molecular consequence:

NM_000256.3:c.1112C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000623516	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 2, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27600940, 20359594, 27483260, 28492532
SCV004839113	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 8, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20359594, 32228044, 32841044, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000623516

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 2, 2019)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004839113

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 8, 2024)

germline

clinical testing

PubMed (4)
[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

Citations

PubMed

Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy.

Cecconi M, Parodi MI, Formisano F, Spirito P, Autore C, Musumeci MB, Favale S, Forleo C, Rapezzi C, Biagini E, Davì S, Canepa E, Pennese L, Castagnetta M, Degiorgio D, Coviello DA.

Int J Mol Med. 2016 Oct;38(4):1111-24. doi: 10.3892/ijmm.2016.2732. Epub 2016 Sep 7.

PubMed [citation]

PMID:: 27600940
PMCID:: PMC5029966

A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort.

Rubattu S, Bozzao C, Pennacchini E, Pagannone E, Musumeci BM, Piane M, Germani A, Savio C, Francia P, Volpe M, Autore C, Chessa L.

Int J Mol Sci. 2016 Jul 30;17(8). doi:pii: E1239. 10.3390/ijms17081239.

PubMed [citation]

PMID:: 27483260
PMCID:: PMC5000637

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000623516.6

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

Description

This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 371 of the MYBPC3 protein (p.Pro371Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27600940, 20359594, 27483260). However, in at least one of these individuals pathogenic allele[s] were also identified in MYBPC3, which suggests that this c.1112C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 42505). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain.

#	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, SCV004839113.1

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

Description

This missense variant replaces proline with arginine at codon 371 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 20359594, 32228044, 32841044). All of these individuals also carried the pathogenic p.Lys1065Glnfs*12 truncation variant in the same gene (ClinVar Variation ID: 42693). This p.Pro371Arg variant has not been identified 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		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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