ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1223+1G>A (rs730880639)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000158340 SCV000927543 likely pathogenic not provided 2018-02-22 criteria provided, single submitter clinical testing
GeneDx RCV000158340 SCV000208275 pathogenic not provided 2013-01-15 criteria provided, single submitter clinical testing Although the c.1223+1 G>A mutation in the MYBPC3 gene has not been previously published as a disease-causing mutation, two different nucleotide substitutions at the same position (c.1223 G>T, c.1223 G>C) have been reported in association with HCM. The c.1223+1 G>A mutation destroys the canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message, which is subjected to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. In addition, c.1223+1 G>A has been observed in multiple other unrelated individuals tested for HCM. The variant is found in HCM panel(s).
Invitae RCV000540594 SCV000623518 likely pathogenic Hypertrophic cardiomyopathy 2017-07-12 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 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: 181066). 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.

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