ClinVar Miner

Submissions for variant NM_000132.3(F8):c.6103G>A (p.Val2035Met) (rs1057521074)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000442362 SCV000520948 pathogenic not provided 2017-01-11 criteria provided, single submitter clinical testing The V2035M variant in the F8 gene has been reported previously in one individual with hemophilia A (Reitter et al., 2010) and in four additional individuals in the Factor VIII Variant Database (http://www.factorviii-db.org). The V2035M variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V2035M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (V2035E, V2035G,V2035A) and in nearby residues (S2030N, Y2036C, N2038S, C2040R, C2040G, C2040Y) have been reported in the Human Gene Mutation Database in association with hemophilia A (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. Therefore, we interpret V2035M as a pathogenic variant.

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