ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.821+5G>A

dbSNP: rs397516077
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Total submissions: 11
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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 RCV000768466 SCV000059323 likely pathogenic Hypertrophic cardiomyopathy 2014-06-19 criteria provided, single submitter clinical testing The 821+5G>A variant in MYBPC3 has been reported in 2 individuals with HCM, was absent from 400 control chromosomes, and segregated with disease in 4 affected r elatives from 1 family (Carrier 1997, Richard 2003). In addition, this variant h as been identified by our laboratory in 2 Caucasian adults with HCM. This varian t is located in the 5' splice region and in vitro studies indicate this variant leads to aberrant splicing which is predicted to result in a truncated or absent protein (Carrier 1997, Flavigny 1999, Flavigny 2003). In summary, segregation a nd in vitro studies suggest that this variant is likely pathogenic, though addit ional studies are required to fully establish its clinical significance.
Center for Medical Genetics Ghent, University of Ghent RCV000009138 SCV000299247 likely pathogenic Hypertrophic cardiomyopathy 4 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000598548 SCV000709898 pathogenic not provided 2021-01-07 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Published functional studies demonstrate that this variant leads to exon skipping and premature truncation (Carrier et al., 1997; Flavigny et al., 1999; Ito et al., 2017); Reported in ClinVar (ClinVar Variant ID# 42796; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31513939, 24721642, 28679633, 10610770, 9048664, 20624503, 12707239, 14613868, 30847666, 33673806)
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000009138 SCV000744865 uncertain significance Hypertrophic cardiomyopathy 4 2017-09-14 criteria provided, single submitter clinical testing
Center for Human Genetics, University of Leuven RCV000768466 SCV000886748 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000770376 SCV000901817 likely pathogenic Cardiomyopathy 2017-02-02 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000598548 SCV000927327 pathogenic not provided 2017-07-04 criteria provided, single submitter clinical testing
Invitae RCV000768466 SCV001414711 pathogenic Hypertrophic cardiomyopathy 2023-10-16 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 9048664, 12707239, 23140321). This variant is also known as IVS7+5G>A. ClinVar contains an entry for this variant (Variation ID: 42796). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7 and introduces a premature termination codon (PMID: 9048664). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000009138 SCV002577578 likely pathogenic Hypertrophic cardiomyopathy 4 2022-05-16 criteria provided, single submitter clinical testing PM2, PP3, PP5
OMIM RCV000009138 SCV000029355 pathogenic Hypertrophic cardiomyopathy 4 1997-03-01 no assertion criteria provided literature only
Clinical Genetics, Academic Medical Center RCV000598548 SCV001922902 uncertain significance not provided no assertion criteria provided clinical testing

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