Submissions for variant NM_000256.3(MYBPC3):c.3627+2del

dbSNP: rs1555120258

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619318	SCV000737353	pathogenic	Cardiovascular phenotype	2020-07-21	criteria provided, single submitter	clinical testing	The c.3627+2delT intronic pathogenic mutation is located 2 nucleotides after coding exon 32 of the MYBPC3 gene. This variant results from a deletion of one nucleotide at position c.3627+2. This alteration has been previously reported in an Egyptian patient with hypertrophic cardiomyopathy (Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80). Another alteration impacting the same donor site (c.3627+1G>A, also referred to as Int33DSG+1A) has been detected in individuals with hypertrophic cardiomyopathy (HCM), confirmed to co-segregate with disease, and reported to produce aberrant RNA splicing (Niimura H et al. N. Engl. J. Med., 1998 Apr;338:1248-57). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae	RCV001254764	SCV002235520	pathogenic	Hypertrophic cardiomyopathy	2021-04-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23233322, 19659763). ClinVar contains an entry for this variant (Variation ID: 519195). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 32 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).
GeneDx	RCV002282267	SCV002571591	pathogenic	not provided	2022-08-31	criteria provided, single submitter	clinical testing	Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (Kassem et al., 2013); 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23233322)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001254764	SCV001430864	likely pathogenic	Hypertrophic cardiomyopathy	2020-01-20	no assertion criteria provided	research	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us.