Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000629020 | SCV000749930 | pathogenic | Hypertrophic cardiomyopathy | 2022-07-16 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 525038). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 22857948; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 18 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). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002404720 | SCV002712986 | likely pathogenic | Cardiovascular phenotype | 2022-08-31 | criteria provided, single submitter | clinical testing | The c.1790+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 18 of the MYBPC3 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. 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 likely pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317306 | SCV004020522 | likely pathogenic | Primary familial hypertrophic cardiomyopathy | 2023-06-19 | criteria provided, single submitter | clinical testing | Variant summary: MYBPC3 c.1790+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 166884 control chromosomes (gnomAD). c.1790+1G>A has been reported in the literature in an individual affected with Hypertrophic Cardiomyopathy (Olivotto_2008). These data do not allow any definitive conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 18533079). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |