ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3491-2A>T

gnomAD frequency: 0.00001  dbSNP: rs397516022
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000464319 SCV000059243 pathogenic Hypertrophic cardiomyopathy 2012-04-18 criteria provided, single submitter clinical testing The 3491-2A>T variant (MYBPC3) has been identified in three individuals with HCM tested by our laboratory. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing lea ding to an abnormal or absent protein. Heterozygous loss of function of the MYBP C3 gene is an established disease mechanism in HCM. In summary, this variant mee ts our criteria for pathogenicity (http://pcpgm.partners.org/LMM).
GeneDx RCV000443859 SCV000516855 likely pathogenic not provided 2024-10-08 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: 27532257, 31006259, 37652022, 25611685, 30282064)
Labcorp Genetics (formerly Invitae), Labcorp RCV000464319 SCV000546428 pathogenic Hypertrophic cardiomyopathy 2025-01-11 criteria provided, single submitter clinical testing This sequence change affects an acceptor 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 clinical features of hypertrophic cardiomyopathy (PMID: 23283745, 25611685, 27532257, 30282064). ClinVar contains an entry for this variant (Variation ID: 42717). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000443859 SCV001433206 likely pathogenic not provided 2019-11-15 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV000443859 SCV002503531 pathogenic not provided 2021-08-16 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV003314558 SCV004014666 pathogenic Hypertrophic cardiomyopathy 4 2023-05-12 criteria provided, single submitter clinical testing The MYBPC3 c.3491-2A>T variant results in a substitution at the consensus splice acceptor site, which may result in splicing defects. This variant has been reported in at least five unrelated individuals with hypertrophic cardiomyopathy (PMID: 25611685; PMID: 30282064; PMID: 31006259). This variant has been classified as pathogenic by at least three submitters in ClinVar. This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Additionally, other substitutions at this same splice acceptor junction, such as c.3491-1G>A and c.3491-3C>G, have been reported in other patients with hypertrophic cardiomyopathy (PMID: 23283745; PMID: 30645170). Based on the available evidence, the c.3491-2A>T variant is classified as pathogenic for hypertrophic cardiomyopathy.
Baylor Genetics RCV003333007 SCV004040665 pathogenic Left ventricular noncompaction 10 2023-05-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV003314558 SCV004041117 pathogenic Hypertrophic cardiomyopathy 4 2023-05-08 criteria provided, single submitter clinical testing

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