NM_000256.3(MYBPC3):c.3005G>A (p.Arg1002Gln) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 5, 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:: RCV000688819.9

Allele description [Variation Report for NM_000256.3(MYBPC3):c.3005G>A (p.Arg1002Gln)]

NM_000256.3(MYBPC3):c.3005G>A (p.Arg1002Gln)

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.3005G>A (p.Arg1002Gln)

Other names:

p.R1002Q:CGG>CAG

HGVS:

NC_000011.10:g.47333742C>T
NG_007667.1:g.23961G>A
NM_000256.3:c.3005G>AMANE SELECT
NP_000247.2:p.Arg1002Gln
LRG_386t1:c.3005G>A
LRG_386:g.23961G>A
LRG_386p1:p.Arg1002Gln
NC_000011.9:g.47355293C>T
Q14896:p.Arg1002Gln

Protein change:

R1002Q

Links:

UniProtKB: Q14896#VAR_029423; dbSNP: rs727504235

NCBI 1000 Genomes Browser:

rs727504235

Molecular consequence:

NM_000256.3:c.3005G>A - 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
SCV000816443	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 18, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11815426, 27532257, 28790153, 28807990, 29030401, 33673806, 33782553, 28492532
SCV004836676	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 5, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11815426, 27532257, 28790153, 28807990, 32841044, 33495597, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000816443

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 18, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004836676

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Feb 5, 2024)

germline

clinical testing

PubMed (7)
[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	22	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients.

Cirino AL, Lakdawala NK, McDonough B, Conner L, Adler D, Weinfeld M, O'Gara P, Rehm HL, Machini K, Lebo M, Blout C, Green RC, MacRae CA, Seidman CE, Ho CY; MedSeq Project*..

Circ Cardiovasc Genet. 2017 Oct;10(5). doi:pii: e001768. 10.1161/CIRCGENETICS.117.001768.

PubMed [citation]

PMID:: 29030401
PMCID:: PMC5683423

Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients.

Hathaway J, Heliö K, Saarinen I, Tallila J, Seppälä EH, Tuupanen S, Turpeinen H, Kangas-Kontio T, Schleit J, Tommiska J, Kytölä V, Valori M, Muona M, Sistonen J, Gentile M, Salmenperä P, Myllykangas S, Paananen J, Alastalo TP, Heliö T, Koskenvuo J.

BMC Cardiovasc Disord. 2021 Mar 5;21(1):126. doi: 10.1186/s12872-021-01927-5.

PubMed [citation]

PMID:: 33673806
PMCID:: PMC7934228

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000816443.6

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

Description

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). 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.

#	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, SCV004836676.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	22	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces arginine with glutamine at codon 1002 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 performed for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 11815426, 28790153, 27532257, 32841044, 33495597; Burns, thesis 2019) and in an 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		22	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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