ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.821+5G>A (rs397516077)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 Familial hypertrophic cardiomyopathy 4 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000598548 SCV000709898 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing The c.821+5G>A variant in the MYBPC3 gene has been reported previously in association with hypertrophic cardiomyopathy (Carrier et al., 1997; Millat et al., 2010). This variant is predicted to affected the canonical splice donor site of intron 7. Functional studies show the c.821+5G>A variant leads to exon skipping and premature truncation (Carrier et al., 1997; Ito et al., 2017). The c.821+5G>A variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.821+5G>A as a pathogenic variant.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000009138 SCV000744865 uncertain significance Familial 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 2019-11-20 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 23140321, 9048664, 12707239). ClinVar contains an entry for this variant (Variation ID: 42796). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 9048664). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009138 SCV000029355 pathogenic Familial hypertrophic cardiomyopathy 4 1997-03-01 no assertion criteria provided literature only

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