ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3815-1G>A (rs397516044)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618617 SCV000739990 likely pathogenic Cardiovascular phenotype 2016-07-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Blueprint Genetics RCV000208066 SCV000264063 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000158273 SCV000208208 likely pathogenic not provided 2018-03-20 criteria provided, single submitter clinical testing The c.3815-1 G>A likely pathogenic variant in the MYBPC3 gene has previously been reported in association with HCM (Alfares et al., 2015; Walsh et al., 2017). This variant has also been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. The c.3815-1 G>A variant destroys the canonical splice acceptor site in intron 33 and is predicted to cause skipping of exon 34, the last coding exon of the MYBPC3 gene. Skipping of exon 34 would result in the loss of 3 amino acid residues and the natural termination codon, ultimately leading to extension of the protein length by using non-coding exon 35. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Other splice site variants in the MYBPC3 gene, and one downstream nonsense variant, have been reported in HGMD in association with HCM (Stenson et al., 2014). Furthermore, the c.3815-1 G>A variant is not observed at significant frequency in large population cohorts (Lek et al., 2016).
Gharavi Laboratory,Columbia University RCV000158273 SCV000809457 pathogenic not provided 2018-09-16 no assertion criteria provided research
Invitae RCV000701771 SCV000830587 uncertain significance Hypertrophic cardiomyopathy 2018-09-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 33) of the MYBPC3 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hypertrophic cardiomyopathy and in an individual referred for genetic testing (PMID: 25611685, 27532257). ClinVar contains an entry for this variant (Variation ID: 42746). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000701771 SCV000059272 likely pathogenic Hypertrophic cardiomyopathy 2011-09-30 criteria provided, single submitter clinical testing The 3815-1G>A variant has not been previously reported or been identified by our laboratory. This variant is predicted to cause abnormal splicing because the nu cleotide substitution occurs in the highly conserved splice consensus sequence. Pathogenic splice variants in MYBPC3 are common in patients with HCM, which sup ports a disease causing role.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000208066 SCV000747923 likely pathogenic Primary familial hypertrophic cardiomyopathy 2016-12-23 criteria provided, single submitter clinical testing

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