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

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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, Mass General Brigham 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	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
Invitae	RCV000211787	SCV001381270	pathogenic	Hypertrophic cardiomyopathy	2023-02-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met348Thrfs*4) in 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 (PMID: 19574547). This variant is present in population databases (rs730880336, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23711808, 27532257, 29907873). ClinVar contains an entry for this variant (Variation ID: 177698). For these reasons, this variant has been classified as Pathogenic.

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