ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2905C>T (p.Gln969Ter) (rs397515992)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158195 SCV000208130 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing The pathogenic Q969X variant in the MYBPC3 gene has been reported previously in several unrelated patients with HCM, and has been reported to co-segregate with HCM in more than 25 relatives from three different families (Yu et al., 1998; Van Driest et al., 2004; Olivotto et al., 2008; Roncarati et al., 2011; Page et al., 2012; Berge et al., 2014; Murphy et al., 2016; McTaggart et al., 2016). The Q969X variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Q969X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Furthermore, other pathogenic nonsense variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014).
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201916 SCV000256641 pathogenic Familial hypertrophic cardiomyopathy 1 2015-07-21 criteria provided, single submitter research The MYBPC3 Gln969* variant has been observed in multiple unrelated HCM cases (Roncarati R, et al., 2011; Van Driest SL, et al., 2004; Yu B, et al., 1998) and absent in >150 controls (Van Driest SL, et al., 2004; Roncarati R, et al., 2011). Furthermore, this variant is absent from both the 1000 genomes project (http://www.1000genomes.org/) and Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified the MYBPC3 Gln969* variant in an HCM family where two additional variants in MYBPC3 (Arg668His; "uncertain significance") and MYH7 (Arg1079Gln; "uncertain significance") have also been observed in the family (Girolami F, et al., 2010). MYPBC3 Gln969* was identified in our HCM proband who carried the additional MYH7 Arg1079Gln variant. The proband's affected sister carries this MYBPC3 Gln969* as well as both additional MYBPC3 and MYH7 variants variants (Girolami F, et al., 2010). This MYBPC3 variant results in a premature stop codon in place of glutamine (Gln) at position 969 and predicted to result in a truncated protein. Given that loss-of-function variants in MYBPC3 are an established mechanism of disease in HCM, and that MYBPC3 Gln969* has been observed in other cases of familial HCM, we classify this variant as "pathogenic".
Invitae RCV000547495 SCV000623577 pathogenic Hypertrophic cardiomyopathy 2017-04-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 969 (p.Gln969*) of the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic. This particular variant has been reported in the literature in individuals and families with hypertrophic cardiomyopathy (PMID: 9541104, 27532257). ClinVar contains an entry for this variant (Variation ID: 42669). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000606843 SCV000743544 pathogenic Familial hypertrophic cardiomyopathy 4 2016-05-26 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000547495 SCV000747757 pathogenic Hypertrophic cardiomyopathy 2017-11-20 criteria provided, single submitter clinical testing This heterozygous nonsense variant in the MYBPC3 gene was identified in a male patient (53 years old) with familial hypertrophic cardiomyopathy
Blueprint Genetics RCV000158195 SCV000928262 pathogenic not provided 2019-03-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000547495 SCV000059190 pathogenic Hypertrophic cardiomyopathy 2011-11-18 no assertion criteria provided clinical testing The Gln969X variant has been reported in the literature in at least 2 individual s with clinical features of HCM (Yu 1998, Van Driest 2004) and in our laboratory in three other individuals with HCM. The Gln969X variant leads to a premature s top at codon 969. This alteration is predicted to lead to a truncated or absent protein. Loss of function variants are an established mechanism of disease for t he MYBPC3 gene. It should be noted that this variant was seen in one family alo ng with a second likely pathogenic variant, suggesting that this variant may hav e a milder effect. In summary, the Gln969X variant is highly likely to be patho genic.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000606843 SCV000733032 pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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