ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3181C>T (p.Gln1061Ter) (rs397516005)

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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, Partners HealthCare Personalized Medicine RCV000628946 SCV000059213 pathogenic Hypertrophic cardiomyopathy 2012-07-12 criteria provided, single submitter clinical testing The Gln1061X variant in MYBPC3 has been reported in the literature in six HCM pr obands, segregated in 12 affected or clinically suspicious relatives across five families and was absent from 328 healthy control chromosomes (Jaaskelaine 2002, Poutanen 2006). The families were all of Finnish ancestry, and haplotype analys is suggests that this variant could be a founder mutation in this population (Ja askelaine 2002). In addition, this variant has not been identified in large and broad populations by the NHLBI Exome Sequencing Project (http://evs.gs.washingto n.edu/EVS). Gln1061X is a nonsense variant leading to a premature termination co don at position 1061, which is predicted to lead to a truncated or absent protei n. Heterozygous loss of function of the MYBPC3 gene is an established disease me chanism in HCM patients. In summary, this variant meets our criteria to be class ified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studi es, absence from controls, and established disease mechanism.
Blueprint Genetics RCV000035563 SCV000188789 pathogenic Primary familial hypertrophic cardiomyopathy 2015-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000158219 SCV000208154 pathogenic not provided 2013-03-18 criteria provided, single submitter clinical testing This mutation is dentoed p.Gln1061Stop (CAG>TAG): c.3181 C>T in exon 29 of the MYBPC3 gene (NM_000256.3). The Gln1061Stop mutation in the MYBPC3 gene has been reported in association with HCM (Jaaskelainen P et al., 2002). Jaaskelainen et al. identified Gln1061Stop in 6 unrelated families with HCM from Finland, and it was not observed in 200 control chromosomes. This study reported this mutation co-segregated with HCM in multiple families and suggested Gln1061Stop may be a founder mutation in the Finnish population. Gln1061Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the MYBPC3 gene have been reported in association with HCM. In summary, Gln1061Stop in the MYBPC3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Ambry Genetics RCV000619311 SCV000739930 pathogenic Cardiovascular phenotype 2016-02-26 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes)
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625352 SCV000745032 pathogenic Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Invitae RCV000628946 SCV000749854 pathogenic Hypertrophic cardiomyopathy 2019-08-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1061*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs397516005, ExAC 0.02%). This variant has been reported in numerous individuals affected with hypertrophic cardiomyopathy (PMID: 12110947, 27532257, 26267065 ), and has been reported to be present in a high proportion of affected individuals with Finnish ancestry (PMID: 22462493) .ClinVar contains an entry for this variant (Variation ID: 42690). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171135 SCV001333816 pathogenic Cardiomyopathy 2018-05-10 criteria provided, single submitter clinical testing
Color RCV001171135 SCV001348901 pathogenic Cardiomyopathy 2019-11-25 criteria provided, single submitter clinical testing

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