Submissions for variant NM_001360016.2(G6PD):c.404A>C (p.Asn135Thr)

dbSNP: rs782322505

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059211	SCV001223828	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 135 of the G6PD protein (p.Asn135Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 22906837, 27519946). This variant is also known as G6PD Cairo. ClinVar contains an entry for this variant (Variation ID: 854215). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt G6PD protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001091837	SCV001248071	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	G6PD: PM2, PM5, PS3:Moderate, PS4:Moderate, PP1, PP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001091837	SCV001472687	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	The G6PD c.404A>C; p.Asn135Thr variant (rs782322505), also known as c.494A>C; p.Asn165Thr (NM_000402.4) and G6PD Cairo, is reported in the literature in several children with acute hemolytic anemia induced by favism; all affected children demonstrated hyperbilirubinemia and were deficient for G6PD enzyme activity (Al-Sweedan 2012, Beutler 2002, Doss 2016, Reading 2016, Sirdah 2017). This variant is reported in ClinVar (Variation ID: 854215) and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.887). Based on available information, this variant is considered to be pathogenic. References: Al-Sweedan SA et al. Molecular characterization of glucose-6-phosphate dehydrogenase deficiency among Jordanians. Acta Haematol. 2012 128:195-202. PMID: 22906837. Beutler E et al. Hematologically important mutations: glucose-6-phosphate dehydrogenase. Blood Cells Mol Dis. 2002 28:93-103. PMID: 12064901. Doss CG et al. Genetic Epidemiology of Glucose-6-Phosphate Dehydrogenase Deficiency in the Arab World. Sci Rep. 2016 6:37284. PMID: 27853304. Reading NS et al. Favism, the commonest form of severe hemolytic anemia in Palestinian children, varies in severity with three different variants of G6PD deficiency within the same community. Blood Cells Mol Dis. 2016 60:58-64. PMID: 27519946. Sirdah MM et al. Possible association of 3' UTR +357 A>G, IVS11-nt 93 T>C, c.1311 C>T polymorphism with G6PD deficiency. Hematology. 2017 22:370-374. PMID: 28059001.
Dunham Lab, University of Washington	RCV001059211	SCV002599329	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in unrelated hemizygotes with deficiency, anemia, and favism (PS4_M, PP4). Decreased activity in red blood cells (4-20%) (PS3). Predicted to be damaging by SIFT and probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by CeGaT (PP5). Post_P 0.997 (odds of pathogenicity 3155, Prior_P 0.1).
Revvity Omics, Revvity	RCV001059211	SCV003822585	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-05-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467799	SCV004195405	pathogenic	Malaria, susceptibility to	2024-03-16	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001091837	SCV005197996	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782632	SCV005394460	pathogenic	G6PD deficiency	2024-09-13	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.494A>C (p.Asn165Thr), corresponding to c.404A>C (p.Asn135Thr) in NM_001042351 and also referred to as G6PD Cairo, results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183369 control chromosomes. c.494A>C has been reported in the literature in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. Sirdah_2012, Al-Sweedan_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22770933, 22906837). ClinVar contains an entry for this variant (Variation ID: 854215). Based on the evidence outlined above, the variant was classified as pathogenic.
Breakthrough Genomics, Breakthrough Genomics	RCV001059211	SCV004243585	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2021-07-15	no assertion criteria provided	clinical testing