ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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).
Blueprint Genetics RCV000208066 SCV000264063 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618617 SCV000739990 likely pathogenic Cardiovascular phenotype 2020-03-25 criteria provided, single submitter clinical testing The c.3815-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 34 of the MYBPC3 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
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
Invitae RCV000701771 SCV000830587 uncertain significance Hypertrophic cardiomyopathy 2020-10-05 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 individuals with clinical features of hypertrophic cardiomyopathy (PMID: 25611685, 27532257, Invitae). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264482 SCV001442656 uncertain significance not specified 2020-10-26 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.3815-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The potentially skipped exon (exon 34) only encodes the last 3 amino acids of the protein. Thus the consequence of skipping of exon 34 is not clear. The variant allele was found at a frequency of 4.1e-06 in 242650 control chromosomes. c.3815-1G>A has been reported in the literature in at least one individual affected with HCM (Alfares_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five laboratories classified this variant as pathogenic/likely pathogenic, however, the most recent submission classified this variant as VUS. Based on the evidence outlined above, the variant was classified as VUS.
Gharavi Laboratory,Columbia University RCV000158273 SCV000809457 pathogenic not provided 2018-09-16 no assertion criteria provided research

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