Submissions for variant NM_000256.3(MYBPC3):c.1351+2T>C (rs397515897)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158072	SCV000208007	pathogenic	not provided	2017-08-10	criteria provided, single submitter	clinical testing	The c.1351+2 T>C variant in the MYBPC3 gene has been published previously in association with HCM (Alfares et al., 2015). This variant destroys the canonical splice donor site in intron 15 and is predicted to cause abnormal gene splicing. Other splice site variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.1351+2 T>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000656564	SCV000778610	pathogenic	Familial hypertrophic cardiomyopathy 4	2018-05-08	criteria provided, single submitter	research
Invitae	RCV000815508	SCV000955966	likely pathogenic	Hypertrophic cardiomyopathy	2018-12-07	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 and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 42525). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). 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.
Laboratory for Molecular Medicine,Partners HealthCare 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.