Submissions for variant NM_000256.3(MYBPC3):c.1351+1G>C

dbSNP: rs727503204

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000424735	SCV000516833	pathogenic	not provided	2015-04-28	criteria provided, single submitter	clinical testing	Although the c.1351+1 G>C variant has not been reported as pathogenic or as a benignpolymorphism to our knowledge, another substitution for the same position (c.1351+1 G>A) has beenreported in at least two individuals with cardiomyopathy (Ho et al., 2009; Waldmuller et al., 2011). This variant destroys the canonical splice donor site in intron 15 and is predicted to cause abnormal gene splicing. The variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson P et al., 2014).In summary, c.1351+1 G>C in the MYBPC3 gene is interpreted as a pathogenic variant.
Ambry Genetics	RCV002379314	SCV002690189	pathogenic	Cardiovascular phenotype	2024-09-30	criteria provided, single submitter	clinical testing	The c.1351+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 15 of the MYBPC3 gene. This variant has been observed in at least one individual with a personal and/or family history that is consistent with hypertrophic cardiomyopathy (HCM) (Ambry internal data). Another alteration impacting the same donor site (c.1351+1G>A) has been detected in HCM cohorts (Ho CY et al. Circ Cardiovasc Genet, 2009 Aug;2:314-21; Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. In addition to the clinical data presented in the literature, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090721	SCV005832076	pathogenic	Hypertrophic cardiomyopathy	2024-05-02	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 MYBPC3-related conditions (PMID: 31308319; Invitae). ClinVar contains an entry for this variant (Variation ID: 379619). 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.