ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1038_1042dup (p.Met348fs) (rs730880336)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211787 SCV000203958 pathogenic Hypertrophic cardiomyopathy 2013-03-05 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000158423 SCV000208358 pathogenic Cardiomyopathy 2013-05-06 criteria provided, single submitter clinical testing c.1038_1042dupCGGCA: p.Met348ThrfsX4 (M348TfsX4) in exon 12 of the MYBPC3 gene (NM_000256.3). The normal sequence with the bases that are inserted in braces is: GGCA{CGGCA}TGCT.The c.1038_1042dupCGGCA mutation in the MYBPC3 gene has been reported in association with HCM. In addition, this mutation was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.1038_1042dupCGGCA mutation causes a shift in the reading frame beginning with Methionine 348, changing it to a Threonine, and creates a premature stop codon at position 4 of the new reading frame. This mutation is expected to result in an abnormal, truncated protein or in absence of protein from this allele due to mRNA decay. Numerous other frameshift mutations in the MYBPC3 gene have been reported in association with HCM. In summary, c.1038_1042dupCGGCA in the MYBPC3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
GeneDx RCV000483113 SCV000568216 pathogenic not provided 2017-03-24 criteria provided, single submitter clinical testing The c.1038_1042dupCGGCA pathogenic variant in the MYBPC3 gene has been previously reported in at least one Chinese family in association with HCM and was absent from 200 control alleles (Xie et al., 2005; Pan et al., 2006; Liu et al., 2013). It is also reported as a pathogenic variant in ClinVar by at least one other clinical laboratory in association with HCM (ClinVar SCV000203958.3; Landrum et al., 2016). This variant causes a shift in reading frame starting at codon Methionine 348, changing it to a Threonine, and creating a premature stop codon at position 4 of the new reading frame, denoted p.Met348ThrfsX4. 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 downstream frameshift variants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014). Furthermore, c.1038_1042dupCGGCA was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.1038_1042dupCGGCA in the MYBPC3 gene is interpreted as a pathogenic variant.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000158423 SCV000900739 pathogenic Cardiomyopathy 2017-02-03 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845559 SCV000987688 pathogenic Left ventricular noncompaction criteria provided, single submitter clinical testing

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