ClinVar Miner

Submissions for variant NM_001022.4(RPS19):c.184C>T (p.Arg62Trp) (rs104894711)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497714 SCV000589354 pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing The R62W variant has been published previously in association with Diamond-Blackfan anemia, including an assumed de novo occurrence (Draptchinskaia et al., 1999; Konno et al., 2010; Wan et al., 2016). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R62W 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. Functional studies have shown R62W results in severe phenotypic defects in mice and interferes with the binding capacity of the RPS19 protein (Devlin et al., 2010; Schuster et al., 2010). Missense variants in the same residue (R62Q) and in nearby residues (A57P, A58P, S59F, T60P, A61E, L64P) have been reported in the Human Gene Mutation Database in association with Diamond-Blackfan anemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic.
Invitae RCV001065746 SCV001230721 pathogenic Diamond-Blackfan anemia 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 62 of the RPS19 protein (p.Arg62Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Diamond-Blackfan anemia (PMID: 9988267, 12586610, 28102861). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6314). This variant has been reported to affect RPS19 protein function (PMID: 20606162, 20395159). This variant disrupts the p.Arg62 amino acid residue in RPS19. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10753603, 12750732, 15384984, 18412286, 20378560, 17053056, 17082006, 17517689, 16159874, 17726054, 24952648). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000033183 SCV000057019 pathogenic Diamond-Blackfan anemia 1 1999-02-01 no assertion criteria provided literature only

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