ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.436dup (p.Thr146fs) (rs397516049)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000414699 SCV000884163 pathogenic not provided 2017-10-03 criteria provided, single submitter clinical testing The c.436dupA (rs397516049) variant is predicted to result in a truncated or absent protein product. This variant was reported in two patients with hypertrophic cardiomyopathy (HCM), and classified as a pathogenic variant using an algorithm-based approach for rare variants associated with cardiac disease (Walsh, 2017). At least two more affected individuals have been reported with this variant in HCM cohort studies (Murphy, 2016 and Alfares, 2015). This variant is listed in the Genome Aggregation Database (gnomAD) identified on a single chromosome out of 30,952, and has been reported to the ClinVar database as a pathogenic variant (Variation ID: 42751). Based on the following observations this variant is predicted to be pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769363 SCV000900751 pathogenic Cardiomyopathy 2017-09-28 criteria provided, single submitter clinical testing
GeneDx RCV000414699 SCV000490633 pathogenic not provided 2017-09-21 criteria provided, single submitter clinical testing The c.436dupA pathogenic variant in the MYBPC3 gene, also denoted as c.436_437insA due to the use of alternate nomenclature, has been previously reported in individuals with HCM (Alfares et al., 2015; Murphy et al., 2016; Walsh et al., 2017). This variant has also been observed in other individuals referred for HCM genetic testing at GeneDx. The c.436dupA variant causes a shift in reading frame starting at codon threonine 146, changing it to an asparagine, and creating a premature stop codon at position 7 of the new reading frame, denoted p.Thr146AsnfsX7. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other frameshift variants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014). Furthermore, c.436dupA has not been observed in large population cohorts (Lek et al., 2016).
Invitae RCV000693262 SCV000821123 pathogenic Hypertrophic cardiomyopathy 2019-01-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr146Asnfs*7) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 42751). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000693262 SCV000059277 pathogenic Hypertrophic cardiomyopathy 2013-08-02 criteria provided, single submitter clinical testing The Thr146fs variant in MYBPC3 was identified in three individuals with HCM from two families by our laboratory. This frameshift variant is predicted to alter t he protein?s amino acid sequence beginning at position 146 and lead to a prematu re termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating variants in the MYBPC3 gen e are established as pathogenic for HCM. In summary, this variant meets our crit eria to be classified as pathogenic ( based upon a bsence from controls and loss of function of the MYBPC3 gene.

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