Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000158240 | SCV000208175 | likely pathogenic | not provided | 2013-06-04 | criteria provided, single submitter | clinical testing | Although the c.3491-3 C>G variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, this variant is predicted to damage the natural splice acceptor site in intron 31 and to cause abnormal gene splicing. Other splice site mutations in the MYBPC3 gene have been reported in association with HCM. Additionally, the c.3491-3 C>G variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in HCM panel(s). |
Invitae | RCV000628981 | SCV000749891 | likely pathogenic | Hypertrophic cardiomyopathy | 2022-10-16 | criteria provided, single submitter | clinical testing | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 32 and introduces a premature termination codon (PMID: 30645170). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 181010). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25351510, 30645170, 33190526). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 31 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. |
Ambry Genetics | RCV002453540 | SCV002612839 | likely pathogenic | Cardiovascular phenotype | 2019-12-11 | criteria provided, single submitter | clinical testing | The c.3491-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 32 in the MYBPC3 gene. This variant was identified in an individual with a personal and family history of hypertrophic cardiomyopathy; RNA studies in the proband demonstrated exon 32 skipping resulting in a premature protein truncation (Singer ES et al. Circ Genom Precis Med, 2019 01;12:e002368). In addition, this variant was reported in a HCM cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This alteration is predicted to decrease or abolish the efficiency of the native splice acceptor site by the ESEfinder and Human Splicing Finder (HSF), and in silico models; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |