Submissions for variant NM_000256.3(MYBPC3):c.2994+1del

dbSNP: rs2095879886

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001202208	SCV001373313	likely pathogenic	Hypertrophic cardiomyopathy	2022-03-28	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 28 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 933900). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001799047	SCV002042188	likely pathogenic	Cardiomyopathy	2019-09-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004033529	SCV005033677	likely pathogenic	Cardiovascular phenotype	2025-03-05	criteria provided, single submitter	clinical testing	The c.2994+1delG intronic variant, located in intron 28 of the MYBPC3 gene, results from a deletion of one nucleotide within intron 28 of the MYBPC3 gene. This variant was reported in an individual with features consistent with MYBPC3-related hypertrophic cardiomyopathy (McGurk KA et al. Am J Hum Genet, 2023 Sep;110:1482-1495). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.