Submissions for variant NM_000256.3(MYBPC3):c.1351+2T>C

dbSNP: rs397515897

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000815508	SCV000059039	pathogenic	Hypertrophic cardiomyopathy	2011-03-10	criteria provided, single submitter	clinical testing	The 1351+2T>C variant has not been reported in the literature. However, it is pr edicted to cause abnormal splicing because the nucleotide substitution occurs in the highly conserved splice consensus sequence. Loss of function of the MYBPC3 gene is an established disease mechanism in HCM patients and splice site variant s can lead to loss of function by generating less or completely absent protein. Therefore, this variant is highly likely to be causative of HCM.
GeneDx	RCV000158072	SCV000208007	pathogenic	not provided	2024-09-03	criteria provided, single submitter	clinical testing	Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in the published literature; at least one patient also harbored a pathogenic variant in another cardiomyopathy gene (PMID: 25611685, 27532257, 32710830); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 25611685, 27532257, 36264615, 37652022, 36243179, 32710830)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000656564	SCV000778610	pathogenic	Hypertrophic cardiomyopathy 4	2018-05-08	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815508	SCV000955966	pathogenic	Hypertrophic cardiomyopathy	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 15 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 individuals with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 31308319; internal data). ClinVar contains an entry for this variant (Variation ID: 42525). 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.
Fulgent Genetics, Fulgent Genetics	RCV002477064	SCV002778627	likely pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-11-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004984653	SCV005458016	likely pathogenic	Cardiovascular phenotype	2024-08-23	criteria provided, single submitter	clinical testing	The c.1351+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 15 in the MYBPC3 gene. This variant has been reported in individuals with features consistent with hypertrophic cardiomyopathy (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Ambry internal data). RNA studies by one group demonstrated that this alteration resulted in abnormal splicing (Vitale G et al. Can J Cardiol, 2020 Sep;36:1554.e1-1554.e3). 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. 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. 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	RCV000815508	SCV005374527	likely pathogenic	Hypertrophic cardiomyopathy		no assertion criteria provided	research