ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1015C>T (p.Gln339Ter) (rs730880631)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158327 SCV000208262 pathogenic not provided 2013-05-08 criteria provided, single submitter clinical testing p.Gln339Stop (Q339X) CAG>TAG: c.1015 C>T in exon 12 of the MYBPC3 gene (NM_000256.3) Although the Gln339Stop mutation has not been reported previously as a disease-causing mutation, it is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense-mediated mRNA decay. Other nonsense mutations in MYBPC3 (Ser297Stop, Ser311Stop, Tyr340Stop, Gln463Stop) have been reported in association with HCM. The variant is found in HCM panel(s).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158327 SCV000280204 likely pathogenic not provided 2014-12-16 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Gln339Stop Given the strong evidence that nonsense variants in MYBPC3 cause HCM, we consider this variant likely disease-causing. The variant has been seen in at least one case of HCM. This is a nonsense variant predicted to cause either a truncated protein or complete absence of the protein due to nonsense mediated mRNA decay. Nonsense variants in the MYBPC3 gene are a frequent cause of HCM (p.Gln76Stop, p.Tyr79Stop, p.Gly115Stop, p.Pro161Stop, p.Gln425Stop) as are splicing and frameshift variants (see http://genepath.med.harvard.edu, www.biobaseinternational.com/pages). There is also a nearby nonsense variant (Tyr340Stop) associated with HCM. Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). Based on the predicted functional effect on the resulting protein this variant is likely associated with disease. In total the variant has not been seen in ~6500 published controls and publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of 6/19/2013). Of note, there are only four frameshift or nonsense variants listed in that entire cohort at this time. The variant is not listed in dbSNP or 1000 Genomes (as of 6/19/2013).

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