Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV001183100 | SCV001348755 | likely pathogenic | Cardiomyopathy | 2020-01-14 | criteria provided, single submitter | clinical testing | This variant alters the canonical splice acceptor site in intron 25 of the MYBPC3 gene. Splice site prediction tools predict that this variant may abolish the native splice acceptor and create a new splice acceptor in exon 26. Although RNA study has not been performed to confirm the prediction, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 28771489). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. |
Invitae | RCV001876083 | SCV002288441 | likely pathogenic | Hypertrophic cardiomyopathy | 2023-02-16 | 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. This sequence change affects an acceptor splice site in intron 25 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 25351510, 34542152; Invitae). ClinVar contains an entry for this variant (Variation ID: 922805). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. |
Ambry Genetics | RCV002429819 | SCV002740680 | pathogenic | Cardiovascular phenotype | 2018-03-26 | criteria provided, single submitter | clinical testing | The c.2603-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 26 in the MYBPC3 gene. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Lopes LR. et al. Heart 2015 Feb;101(4):294-30; Mademont-Soler I. et al. Plos ONE Aug;12(8):e0181465). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.. |