ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2833_2834del (p.Arg945fs) (rs397515987)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000158380 SCV000706762 pathogenic not provided 2017-03-18 criteria provided, single submitter clinical testing
GeneDx RCV000158380 SCV000208315 pathogenic not provided 2018-07-23 criteria provided, single submitter clinical testing The c.2833_2834delCG variant in the MYBPC3 gene has been reported multiple times in association with familial cardiomyopathy (Anan et al., 2002; Hitomi et al., 2010). Anan et al. (2002) identified c.2833_2834delCG (reported as Del. CG945 using alternate nomenclature) in a 40 yo woman with HCM. The c.2833_2834delCG variant was also found in this patient's father, brother, and cousin, all of whom were clinically diagnosed with HCM (Anan et al., 2002). Hitomi et al. (2010) identified c.2833_2834delCG in 4 out of 176 patients with HCM and in 1 out of 54 patients with DCM. One individual with HCM and the c.2833_2834delCG pathogenic variant had an affected sibling who also harbored this variant (Hitomi et al., 2010).This pathogenic variant causes a shift in reading frame starting at codon Arginine 945, changing it to a Glycine, and creating a premature stop codon at position 105 of the new reading frame, denoted p.Arg945GlyfsX105. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.2833_2834delCG variant was not observed at a significant frequency in large population cohorts (Lek et al., 2016), indicating it is not a common benign variant. In summary c.2833_2834delCG in the MYBPC3 gene is interpreted as a pathogenic variant.
Invitae RCV000818526 SCV000959145 pathogenic Hypertrophic cardiomyopathy 2018-09-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg945Glyfs*105) 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 observed to segregate with hypertrophic cardiomyopathy in several families (PMID: 11835941, 20605413), and has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 20605413, 27532257) and dilated cardiomyopathy (PMID: 20605413). This variant is also known as Del CG945 in the literature. ClinVar contains an entry for this variant (Variation ID: 42660). 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 RCV000818526 SCV000059180 pathogenic Hypertrophic cardiomyopathy 2007-04-16 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158380 SCV000280248 likely pathogenic not provided 2012-01-24 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.Arg945Glyfs*105 Given the type of variant, the case data, the segregation data and the absence in samples not selected for HCM (reviewed below) we consider this variant likely disease causing. The variant has been seen in at least 5 patients with cardiomyopathy, not including this patient. Anan et al (2002) reported the variant in four family members with HCM (referred to as Del. CG945). Hitomi et al (2010) found the variant in 4 of 176 HCM patients and 1 of 54 DCM patients in their Japanese cohort. This is a frame-shifting variant that creates a premature stop codon 105 codons downstream of the variant. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. Many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). In total the variant has not been seen in ~64,438 published controls and individuals from publicly available population datasets. The variant was not observed in the following laboratory and published control samples: 50 individuals (Anan et al 2002), 388 (Hitomi et al 2010). The variant is not listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent, including ~4300 East Asian individuals (matching the ancestry of our patient and most of the published cases (as of December 16th, 2014).

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