Submissions for variant NM_000256.3(MYBPC3):c.3814+1G>A

dbSNP: rs1057521823

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000420219	SCV000524667	likely pathogenic	not provided	2020-06-04	criteria provided, single submitter	clinical testing	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; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30297972)
Invitae	RCV001050458	SCV001214566	uncertain significance	Hypertrophic cardiomyopathy	2019-02-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in the last intron (intron 33) of the MYBPC3 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 25132132). ClinVar contains an entry for this variant (Variation ID: 384022). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798808	SCV002042211	uncertain significance	Cardiomyopathy	2022-03-16	criteria provided, single submitter	clinical testing