Submissions for variant NC_000011.10:g.47338688G>C

dbSNP: rs773882783

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523809	SCV000616795	uncertain significance	not provided	2016-02-11	criteria provided, single submitter	clinical testing	The c.2149-9 C>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. In silico analysis using several splice algorithms predicts that c.2149-9 C>G creates a cryptic splice acceptor site and reduces or completely abolishes the downstream natural splice acceptor site. This 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. The c.2149-9 C>G variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, other splice site variants, two of which affect the same splice acceptor site (c.2149-80 G>A, c.2149-3C>G), have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036194	SCV001199545	likely pathogenic	Hypertrophic cardiomyopathy	2024-09-30	criteria provided, single submitter	clinical testing	This sequence change falls in intron 22 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (internal data). ClinVar contains an entry for this variant (Variation ID: 449067). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics	RCV004639261	SCV005144246	likely pathogenic	Cardiovascular phenotype	2024-08-16	criteria provided, single submitter	clinical testing	The c.2149-9C>G intronic variant results from a C to G substitution 9 nucleotides upstream from coding exon 23 in 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 (Ambry internal data). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.