MYBPC3:c.3330+2T>G AND Primary familial hypertrophic cardiomyopathy

Clinical significance:Pathogenic (Last evaluated: Jan 23, 2013)

Review status:

classified by single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000035580.1

Allele description [Variation Report for MYBPC3:c.3330+2T>G]

Gene:
MYBPC3:myosin binding protein C, cardiac [Gene - OMIM]
Variant type:
single nucleotide variant
Cytogenetic location:
11p11.2
Genomic location:
Preferred name:
MYBPC3:c.3330+2T>G
Other names:
IVS30+2T>G
HGVS:
  • NC_000011.10:g.47333192A>C
  • NG_007667.1:g.24511T>G
  • NM_000256.3:c.3330+2T>G
  • LRG_386t1:c.3330+2T>G
  • LRG_386:g.24511T>G
  • NC_000011.9:g.47354743A>C
  • c.3330+2T>G
Nucleotide change:
IVS30DS, T-G, +2
Links:
OMIM: 600958.0020; dbSNP: 387906397
NCBI 1000 Genomes Browser:
rs387906397
Molecular consequence:
  • NM_000256.3:c.3330+2T>G: splice donor variant [Sequence Ontology: SO:0001575]
Observations:
13

Condition(s)

Name:
Primary familial hypertrophic cardiomyopathy (HCM)
Synonyms:
Cardiomyopathy, Hypertrophic, Familial; Hypertrophic cardiomyopathy
Identifiers:
MedGen: C0949658

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Assertion and evidence details

Submission AccessionSubmitterReview StatusClinical Significance
(Last evaluated)
OriginMethodConsequenceCitations
SCV000059230Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicineclassified by single submitterpathogenic
(Jan 23, 2013)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedAlleles observedFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot provided13not providednot providednot providedclinical testing

Citations

PubMed

Homozygosity for a novel splice site mutation in the cardiac myosin-binding protein C gene causes severe neonatal hypertrophic cardiomyopathy.

Xin B, Puffenberger E, Tumbush J, Bockoven JR, Wang H.

Am J Med Genet A. 2007 Nov 15;143A(22):2662-7.

PubMed [citation]
PMID:
17937428

Shared genetic causes of cardiac hypertrophy in children and adults.

Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE.

N Engl J Med. 2008 May 1;358(18):1899-908. doi: 10.1056/NEJMoa075463. Epub 2008 Apr 9.

PubMed [citation]
PMID:
18403758
PMCID:
PMC2752150
See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000059230.1

#EthnicityAlleles ObservedChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

The 3330+2T>G variant in MYBPC3 has been reported in homozygosity in over 10 Amish individuals with severe neonatal onset HCM, has been identified in heterozygosity in >10 individuals with HCM, and segregated with disease in 2 affected relatives (also reported as IVS31+2T>G, Morita 2008, Xin 2007, Zahka 2008, LMM unpublished data). One study found that only 6 of 41 individuals with this variant in heterozygosity exhibited features of HCM or LVH, suggesting that it may be milder in isolation or have reduced penetrance (De 2011). This variant was shown to cause abnormal splicing that resulted in the skipping of exon 30, which is predicted to lead to a frameshift beginning at codon 1064 and create a premature stop codon 38 amino acids downstream (Xin 2007, Morita 2008). Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our criteria for pathogenicity (http://pcpgm.partners.org/lmm) based on the severity of the variant and the impact on splicing, though it may be milder and have reduced penetrance when present in isolation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodVariant allelesAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providedassert pathogenicitynot providednot provided13not provided

Last Updated: Jun 20, 2014

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