Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000158238 | SCV000208173 | pathogenic | not provided | 2022-10-24 | criteria provided, single submitter | clinical testing | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17947214, 28615295, 20215591, 18957093, 16715312, 25163546, 29121657) |
Invitae | RCV000628980 | SCV000749890 | pathogenic | Hypertrophic cardiomyopathy | 2024-01-03 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 31 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with dilated cardiomyopathy and/or hyperthrophic cardiomyopathy (PMID: 16715312, 28615295, 29121657). It has also been observed to segregate with disease in related individuals. This variant is also known as intron 32+1G>T. ClinVar contains an entry for this variant (Variation ID: 181008). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
Illumina Laboratory Services, |
RCV000779061 | SCV000915527 | likely pathogenic | MYBPC3-Related Disorders | 2018-10-08 | criteria provided, single submitter | clinical testing | The MYBPC3 c.3490+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.3490+1G>T variant has been reported in two studies in which it is found in a total of seven individuals, including six individuals with either dilated or hypertrophic cardiomyopathy from the same family (Zeller et al. 2006; Ehlermann et al. 2008). Another family member who experienced sudden death at the age of 32 was an obligate carrier of the variant based on family history and pedigree analysis. The variant was not found among 430 control individuals with normal systolic and diastolic function, nor was it found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database (Ehlermann et al. 2008). Based on the evidence including the potential impact of splice donor variants, the c.3490+1G>T variant is classified as likely pathogenic for MYBPC3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
Agnes Ginges Centre for Molecular Cardiology, |
RCV000628980 | SCV001156329 | pathogenic | Hypertrophic cardiomyopathy | 2018-10-04 | criteria provided, single submitter | research | This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001375509 | SCV001572357 | pathogenic | Cardiomyopathy | 2021-04-15 | criteria provided, single submitter | clinical testing | Variant summary: MYBPC3 c.3490+1G>T (also reported as IVS32+1 G>T, IVS31+1 G>T) 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: Two predict the variant abolishes a 5 splicing donor site. One predicts the variant weakens a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 233146 control chromosomes (gnomAD). c.3490+1G>T has been reported in the literature in multiple individuals affected with Cardiomyopathy (both hypertrophic and dilated cardiomyopathy) including in a family with clear segregation of the variant with the disease (example: Zeller_2006, Ehlermann_2008, Hershberger_2010, Hoedemaekers_2007, Ross_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Ambry Genetics | RCV002453538 | SCV002616092 | pathogenic | Cardiovascular phenotype | 2023-01-24 | criteria provided, single submitter | clinical testing | The c.3490+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 31 of the MYBPC3 gene. This variant was identified in multiple individuals with hypertrophic or dilated cardiomyopathy (Haas J et al. Eur. Heart J., 2015 May;36:1123-35a; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:e001671; Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948) and was shown to segregate with disease in one family (Zeller R et al. J. Mol. Med., 2006 Aug;84:682-91; Ehlermann P et al. BMC Med. Genet., 2008 Oct;9:95). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. 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. As such, this alteration is classified as a disease-causing mutation. |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000158238 | SCV001954466 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000158238 | SCV001969691 | pathogenic | not provided | no assertion criteria provided | clinical testing |