ClinVar Miner

Submissions for variant NM_001360016.2(G6PD):c.1187C>T (p.Pro396Leu)

dbSNP: rs1557229683
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000540637 SCV000647797 uncertain significance Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2016-12-13 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 396 of the G6PD protein (p.Pro396Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in 2 individuals affected with chronic hemolytic anemia with evidence of segregation in one of the families (PMID: 7959695, Invitae). In addition, a different missense substitution at this codon has been reported de novo in an individual affected with G6PD-deficiency (PMID:26275698). One experimental study has shown that heterozygous females had lower levels of mutant mRNA with this variant as compared to the wild-type mRNA in blood cells, which might indicate a preferential survival of cells where the X inactivation is acting on the mutated chromosome (PMID: 8808605). In summary, this variant is a rare missense change that has been reported in affected individuals and suggested to affect blood cell survival. Additional genetic and functional data are needed to further substantiate the pathogenicity this variant. Therefore, it has been classified as a Variant of Uncertain Significance.
Dunham Lab, University of Washington RCV000540637 SCV002599371 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2022-08-12 criteria provided, single submitter curation Variant found in hemizygote with deficiency and CNSHA (PP4). Decreased activity in red blood cells (1%) (PS3). Predicted to be damaging or deleterious by multiple computational algorithms (PP3). Within dimer interface (PM1). Not found in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1).

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