Submissions for variant NM_000256.3(MYBPC3):c.2737+2_2737+3del

dbSNP: rs1265248322

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, University of Leuven	RCV000768477	SCV000886765	likely pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000768477	SCV001417222	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 26 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). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239, 25611685, 27532257, 31513939; Invitae). This variant is also known as IVS26 Del gt [17773–17774]. ClinVar contains an entry for this variant (Variation ID: 619257). 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.
Ambry Genetics	RCV004649309	SCV005144228	likely pathogenic	Cardiovascular phenotype	2024-04-01	criteria provided, single submitter	clinical testing	The c.2737+2_2737+3delTG intronic variant, located in intron 26 of the MYBPC3 gene, results from a deletion of two nucleotides within intron 26 of the MYBPC3 gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.