ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1838dup (p.Asp613fs) (rs730880649)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201914 SCV000256655 pathogenic Familial hypertrophic cardiomyopathy 1 2015-06-18 criteria provided, single submitter research The MYBPC3 Asp613Glufs*25 variant is a result of a duplication of nucleotide A at codon 1838. The new reading frame ends in a stop codon 24 positions downstream. The variant is absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) and the 1000 genomes project (http://www.1000genomes.org/) as well as the literature. We have identified this variant in 1 HCM proband. The patient was diagnosed aged 64 years, with asymmetric septal hypertophy of 21mm, a history of syncope and no established family history of disease. Based on rarity in the population and that known loss-of-function mutations in the MYBPC3 gene are an established mechanism of disease in HCM, we classify this variant as pathogenic. The individual carries an additional variant: ACTN2 Arg457Cys ("uncertain significance").
GeneDx RCV000223830 SCV000208290 pathogenic not provided 2012-05-08 criteria provided, single submitter clinical testing The c.1838dupA variant in the MYBPC3 gene has not been reported previously in association with HCM or as a benign polymorphism to our knowledge. The c.1838dupA variant causes a shift in reading frame beginning with Aspartic acid codon 613, changing it to a Glutamic acid, and creates a premature stop codon at position 25 of the new reading frame. This variant is expected to result in an abnormal, truncated protein or in absence of protein from this allele due to mRNA decay. Other frameshift variants in the MYBPC3 gene have been reported in association with HCM. In summary, c.1838dupA in the MYBPC3 gene is interpreted as a pathogenic variant.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223830 SCV000280225 likely pathogenic not provided 2012-09-07 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.Asp613GlufsX25 We classify this variant as likely disease-causing, based mainly on the type of variant and gene. This is a frame-shifting variant that creates a premature stop codon 25 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. While this specific variant is novel, 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; there are no frameshift variants listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6000 Caucasian and African American individuals (as of 7/30/2012). The variant has not been reported in dbSNP or 1000Genomes. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6000 Caucasian and African American individuals (as of August 2012).

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