ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1238A>G (p.Glu413Gly) (rs730880532)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158069 SCV000208004 likely pathogenic not provided 2012-04-24 criteria provided, single submitter clinical testing This variant is denoted MYPBC3 c.1238A>G at the cDNA level, p.E413G at the protein level. The E413G variant in the MYBPC3 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. E413G results in a non-conservative amino acid substitution of a negatively charged Glutamic acid residue with an uncharged, non-polar Glycine residue at a position that is conserved through zebra fish. In silico analysis predicts E413G is probably damaging to the protein structure/function (Kumar P et al., 2009; Adzhubei I et al., 2010). Additionally, mutations in nearby codons (G407S, S408N, G416S) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports E413G was not observed in approximately 6,300 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.Therefore, while E413G is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant with the clinical and molecular information available at this time. The variant is found in HCM panel(s).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223683 SCV000280209 uncertain significance not specified 2014-07-22 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.Glu413Gly Based on the data reviewed below we consider this variant as a variant of uncertain significance. This variant is novel and has not been reported previously as a disease mutation or as a benign polymorphism. Glu413Gly results in a non-conservative amino acid substitution of a negatively charged Glutamic acid residue with an uncharged, non-polar Glycine residue at a position that is conserved through zebra fish. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging with a score of 0.998. Mutation Taster predicts the variant to be deleterious with a score of 98. The Glutamic acid at codon 413 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (Gly407Ser; Ser408Asn; Gly416Ser). In total the variant has not been seen in ~6,000 individuals from publicly available population datasets. There is no variation at codon 413 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,000 Caucasian and African American individuals (as of 5/31/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 5/31/13).

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