NM_000256.3(MYBPC3):c.3190+4C>T AND not specified

Clinical significance:Uncertain significance (Last evaluated: Oct 19, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000158221.4

Allele description [Variation Report for NM_000256.3(MYBPC3):c.3190+4C>T]

NM_000256.3(MYBPC3):c.3190+4C>T

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.3190+4C>T
HGVS:
  • NC_000011.10:g.47333553G>A
  • NG_007667.1:g.24150C>T
  • NM_000256.3:c.3190+4C>TMANE SELECT
  • LRG_386t1:c.3190+4C>T
  • LRG_386:g.24150C>T
  • NC_000011.9:g.47355104G>A
Links:
dbSNP: rs571457875
NCBI 1000 Genomes Browser:
rs571457875
Molecular consequence:
  • NM_000256.3:c.3190+4C>T - intron variant - [Sequence Ontology: SO:0001627]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000271993Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Uncertain significance
(Oct 28, 2015)
germlineclinical testing

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

SCV001442816Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Oct 19, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.

Viswanathan SK, Sanders HK, McNamara JW, Jagadeesan A, Jahangir A, Tajik AJ, Sadayappan S.

PLoS One. 2017;12(11):e0187948. doi: 10.1371/journal.pone.0187948.

PubMed [citation]
PMID:
29121657
PMCID:
PMC5679632
See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000271993.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The c.3190+4C>T variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy, but has been identified in 9/16308 South Asian chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs571457875). This variant is located in the 5' splice region. Computational tools do not suggest an impact to splicing. However, this information is not pre dictive enough to rule out pathogenicity. In summary, the clinical significance of the c.3190+4C>T variant is uncertain.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442816.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: MYBPC3 c.3190+4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. Experimental evidence supports these predictions demonstrating the variant does not cause significantly altered splicing in a cell-based minigene assay (Ito_2017). The variant allele was found at a frequency of 9.6e-05 in 238768 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (0.00059 vs 0.001), allowing no conclusion about variant significance. c.3190+4C>T has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Headrick_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.3330+5G>C; Internal testing). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance while one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2021

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