Submissions for variant NM_000256.3(MYBPC3):c.2413+1G>A

dbSNP: rs1595843828

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV005054298	SCV001156296	pathogenic	Hypertrophic cardiomyopathy 4	2018-10-12	criteria provided, single submitter	research	MYBPC3 c.2413+1G>A has been previously identified in 1 DCM proband and was found to segregate with a HCM/DCM phenotype in 4 other affected family members (Ehlermann P, et al., 2008). We identified this variant in a HCM proband of with a family history of HCM, segregation studies however were not possible (Ingles J, et al., 2005; Ingles J, et al., 2017). The variant is very rare, being absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In summary the variant is located in the canonical splice site and MYBPC3 loss of function variant are known mechanism of disease, the variant is also rare, and has been found to segregate with disease, therefore we classify MYBPC3 c.2413+1G>A as 'Pathogenic'.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000999594	SCV003440374	pathogenic	Hypertrophic cardiomyopathy	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 24 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: 9562578, 28615295). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS24+1 and Int24DSG+1. ClinVar contains an entry for this variant (Variation ID: 810754). 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.
Ambry Genetics	RCV004030255	SCV005033769	likely pathogenic	Cardiovascular phenotype	2023-09-23	criteria provided, single submitter	clinical testing	The c.2413+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 24 of the MYBPC3 gene. 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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; 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 variant has been detected in probands with hypertrophic cardiomyopathy and segregated with disease in a family (Niimura H et al. N Engl J Med, 1998 Apr;338:1248-57; Ingles J et al. J Med Genet, 2005 Oct;42:e59; Ehlermann P et al. BMC Med Genet, 2008 Oct;9:95Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV004030255	SCV006065819	likely pathogenic	Cardiovascular phenotype	2024-02-07	criteria provided, single submitter	clinical testing	PVS1_mod, PS4_mod, PM2, PP5