ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2148+1G>T (rs1060499604)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619126 SCV000736411 likely pathogenic Cardiovascular phenotype 2017-04-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477839 SCV000536878 likely pathogenic Familial hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2015-10-03 no assertion criteria provided research
Invitae RCV000702923 SCV000831800 likely pathogenic Hypertrophic cardiomyopathy 2018-05-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 22 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 417931). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000702923 SCV000731715 likely pathogenic Hypertrophic cardiomyopathy 2017-11-03 criteria provided, single submitter clinical testing The c.2148+1G>T variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy or in large population studies but has been reported by ot her clinical laboratories in ClinVar (Variation ID 417931). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predi cted to cause altered splicing leading to an abnormal or absent protein. Heteroz ygous loss of function of the MYBPC3 gene is an established disease mechanism in hypertrophic cardiomyopathy (HCM). In summary, although additional studies are required to fully establish its clinical significance, the c.2148+1G>T variant i s likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).

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