Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000617726 | SCV000739972 | likely pathogenic | Cardiovascular phenotype | 2016-06-17 | criteria provided, single submitter | clinical testing | The c.3330+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 30 of the MYBPC3 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6195 samples (12390 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is likely to be pathogenic (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). |
| Invitae | RCV001390887 | SCV001592753 | pathogenic | Hypertrophic cardiomyopathy | 2020-06-21 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 30 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 17937428, 18403758, 21835286, 25031304). ClinVar contains an entry for this variant (Variation ID: 520283). Experimental studies have shown that disruption of this splice site affects mRNA splicing (PMID: 17937428, 25031304). Donor and acceptor splice site variants 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. |