ClinVar Miner

Submissions for variant NM_000032.5(ALAS2):c.1354C>T (p.Arg452Cys) (rs137852311)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254885 SCV000322292 pathogenic not provided 2017-12-22 criteria provided, single submitter clinical testing The R452C variant has been published previously in association with X-linked sideroblastic anemia (Furuyama et al., 2006; Liu et al., 2013; Ohba et al., 2013). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R452C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. 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. Additionally, functional studies have shown that R452C interferes with the cofactor and succinyl-CoA binding ability of the ALAS2 protein (Bishop et al., 2012). Missense variants in the same residue (R452S/G/H) and in nearby residues (R448Q, H450L) have been reported in the Human Gene Mutation Database in association with sideroblastic anemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.
OMIM RCV000011231 SCV000031458 pathogenic Anemia, sideroblastic, 1 1999-03-01 no assertion criteria provided literature only

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