ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1223+2T>G

dbSNP: rs730880641
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158342 SCV000208277 pathogenic not provided 2014-01-18 criteria provided, single submitter clinical testing c.1223+2 T>G: IVS13+2 T>G in intron 13 of the MYBPC3 gene (NM_000256.3) Although the c.1223+2 T>G mutation has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice donor site in intron 13 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. This mutation was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other splice site mutations in the MYBPC3 gene have been reported in association with HCM. In summary, c.1223+2 T>G in the MYBPC3 gene is interpreted as a disease-causing mutation. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Invitae RCV001222693 SCV001394806 pathogenic Hypertrophic cardiomyopathy 2023-12-12 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. 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27532257, 29497013; Invitae). ClinVar contains an entry for this variant (Variation ID: 181068). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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