ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1224-19G>A (rs587776699)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics, RCV000788553 SCV000927706 likely pathogenic not provided 2018-05-24 criteria provided, single submitter clinical testing
GeneDx RCV000168768 SCV000170461 likely pathogenic not specified 2018-12-18 criteria provided, single submitter clinical testing The c.1224-19G>A likely pathogenic variant in the MYBPC3 gene has been reported in association with hypertrophic cardiomyopathy (Waldmuller et al., 2008; Frank-Hansen et al., 2008; Mendes de Almeida et al., 2017). Additionally, functional studies using mRNA analysis demonstrate that this variant creates a splice acceptor site upstream of the canonical splice acceptor site and adds 17 nucleotides to the transcript (Frank-Hansen et al., 2008). This variant is predicted to result in aberrant gene splicing that leads to protein truncation and frameshift (Frank-Hansen et al., 2018). Furthermore, other deep intronic splice site variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.1224-19 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In summary, c.1224-19G>A in the MYBPC3 gene is interpreted as a likely pathogenic variant.
Invitae RCV000467263 SCV000546477 likely pathogenic Hypertrophic cardiomyopathy 2018-04-29 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the MYBPC3 mRNA. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. This variant is present in population databases (rs587776699, ExAC 0.04%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 18258667, 18337725). ClinVar contains an entry for this variant (Variation ID: 138326). Experimental studies have shown that this intronic change creates a novel splice acceptor site and extends the transcript by 17 nucleotides (PMID: 18337725). 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.
OMIM RCV000009149 SCV000029366 pathogenic Familial hypertrophic cardiomyopathy 4 2008-09-01 no assertion criteria provided literature only

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