NM_000256.3(MYBPC3):c.26-2A>G AND MYBPC3-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 14, 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:: RCV004549422.2

Allele description [Variation Report for NM_000256.3(MYBPC3):c.26-2A>G]

NM_000256.3(MYBPC3):c.26-2A>G

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.26-2A>G

HGVS:

NC_000011.10:g.47351507T>C
NG_007667.1:g.6196A>G
NG_122461.1:g.262T>C
NM_000256.3:c.26-2A>GMANE SELECT
LRG_386t1:c.26-2A>G
LRG_386:g.6196A>G
NC_000011.9:g.47373058T>C
c.26-2A>G

Links:

dbSNP: rs376395543

NCBI 1000 Genomes Browser:

rs376395543

Molecular consequence:

NM_000256.3:c.26-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: MYBPC3-related disorder
Synonyms:: MYBPC3-Related Disorders; MYBPC3-related condition; MYBPC3-related disease
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002107113	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 5, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15519027, 18957093, 23674513, 24510615, 22267749, 27532257, 25741868
SCV004116699	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002107113

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 5, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004116699

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 14, 2023)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy.

Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ, Ackerman MJ.

J Am Coll Cardiol. 2004 Nov 2;44(9):1903-10.

PubMed [citation]

PMID:: 15519027

Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene.

Ehlermann P, Weichenhan D, Zehelein J, Steen H, Pribe R, Zeller R, Lehrke S, Zugck C, Ivandic BT, Katus HA.

BMC Med Genet. 2008 Oct 28;9:95. doi: 10.1186/1471-2350-9-95.

PubMed [citation]

PMID:: 18957093
PMCID:: PMC2584029

See all PubMed Citations (7)

Details of each submission

From DASA, SCV002107113.2

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

Description

The c.26-2A>G variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 42644; PMID: 15519027; PMID: 18957093; PMID: 23674513; PMID: 24510615; PMID: 22267749; PMID: 27532257) - PS4. The variant is present at low allele frequencies population databases (rs376395543 – gnomAD 0.0002741%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 18957093; 22267749) - PP1_strong. In summary, the currently available evidence indicates that the variant is 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		1	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV004116699.1

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

Description

The MYBPC3 c.26-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in multiple patients with hypertrophic cardiomyopathy (Ehlermann et al. 2008. PubMed ID: 18957093; Witjas-Paalberends et al. 2013. PubMed ID: 23674513; Kapplinger et al. 2014. PubMed ID: 24510615). This variant is reported in 0.0052% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47373058-T-C). Variants that disrupt the consensus splice acceptor site in MYBPC3 are expected to be pathogenic. This variant is interpreted 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

Last Updated: Nov 24, 2024

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