ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3019T>C (p.Trp1007Arg) (rs730880585)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158208 SCV000208143 likely pathogenic not provided 2014-03-30 criteria provided, single submitter clinical testing This variant is denoted p.Trp1007Arg (TGG>CGG): c.3019 T>C in exon 29 of the MYBPC3 gene (NM_000256.3). The Trp1007Arg variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, but has been observed in other unrelated individuals tested for HCM. Trp1007Arg results in a non-conservative amino acid substitution of a non-polar Tryptophan with a positively-charged Arginine at a position that is conserved across species. In silico analysis predicts Trp1007Arg is damaging to the protein structure/function. In addition, mutations in nearby residues (Arg1002Gln, Glu1017Lys) have been reported in association with HCM, supporting the functional importance of this region of the protein. Furthermore, Trp1007Arg 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. In summary, Trp1007Arg in the MYBPC3 gene is a good candidate for a disease-causing mutation. The variant is found in HCM panel(s).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223707 SCV000280255 uncertain significance not specified 2011-11-30 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. p.Trp1007Arg (W1007R; c.3019T>C) in the MYBPC3 gene. This variant is novel. It has not been reported in association with HCM to date. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (score: 1.00). Mutation taster predicts this change to be damaging with a score of 101. SIFT predicts this change to be damaging with a median information content of 3.12. The Tryptophan at codon 1007 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon and nearby codons. This is a conservative amino acid change with a non polar, neutral Tryptophan replaced with a polar, positive Arginine In total the variant has not been seen in 6,900 published controls and individuals from publicly available population datasets. Familion reports this variant has not been observed in an internal control population of over 400 unrelated, ethnically diverse individuals. There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 5/2/13). There is no variation at codon 1007 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6,500 Caucasian and African American individuals (as of 5/2/13). Note that this dataset does not match the patient's ancestry.

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