ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3490+1G>T

gnomAD frequency: 0.00001  dbSNP: rs397516020
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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, Illumina 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, Centenary Institute 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, LabCorp 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, Radboudumc and MUMC+ RCV000158238 SCV001954466 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000158238 SCV001969691 pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.