ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2308+1G>T

dbSNP: rs112738974
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000230791 SCV000059127 pathogenic Hypertrophic cardiomyopathy 2017-05-04 criteria provided, single submitter clinical testing The c.2308+1G>T variant in MYBPC3 has been reported in 1 individual with HCM and segregated with disease in 4 affected relatives (Niimura 1998). This variant ha s also been identified by our laboratory in 1 individual with LVH. It has not be en identified in large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause alte red splicing leading to an abnormal or absent protein. In addition, functional studies indicate this variant leads to aberrant splicing (Niimura 1998). Heteroz ygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with cardiomyopathy. In summary, this variant meets criteria to be classified as pathogenic for cardiomyopathy in an autosomal dominant manner.
GeneDx RCV000158148 SCV000208083 pathogenic not provided 2023-10-19 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 9562578, 27532257)
Invitae RCV000230791 SCV000284224 pathogenic Hypertrophic cardiomyopathy 2022-10-07 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 42611). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18957093). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 23 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547).

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