Submissions for variant NM_000402.4(G6PD):c.233T>C (p.Ile78Thr)

gnomAD frequency: 0.00001  dbSNP: rs76645461

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224890	SCV000280664	pathogenic	not provided	2015-01-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704108	SCV000833043	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 48 of the G6PD protein (p.Ile48Thr). This variant is present in population databases (rs76645461, gnomAD 0.02%). This missense change has been observed in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (PMID: 8490627, 16119988, 22018328, 22963789). This variant is also known as the Aures variant. ClinVar contains an entry for this variant (Variation ID: 10402). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on G6PD protein function. Experimental studies have shown that this missense change affects G6PD function (PMID: 8490627, 22963789). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000704108	SCV001142115	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000704108	SCV001523185	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2020-07-27	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000224890	SCV001793238	pathogenic	not provided	2024-08-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20236109, 8787363, 27853304, 12972027, 8860007, 16119988, 22963789, 22018328, 21931771, 27884173, 8490627, 34272389, 31589614, 37644014, 37967096, 36681081, 36212142, 28902532, 23006493)
Revvity Omics, Revvity	RCV000704108	SCV002025185	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-05-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001796957	SCV002038576	pathogenic	G6PD deficiency	2021-06-16	criteria provided, single submitter	clinical testing	The G6PD c.233T>C (p.Ile78Thr) variant is a missense variant. Across a selection of the available literature, this variant, which is also known as the G6PD Aures variant, has been reported in 92 individuals with glucose-6-phosphate dehydrogenase deficiency, including in a hemizygous state in 66 males, in a homozygous state in 15 females, and in 11 cases of unspecified sex/zygosity (Nafa et al. 1993; AlFadhli et al. 2005; Al-Jaouni et al. 2011; Dallol et al. 2012; Benmansour et al. 2013; Sanephonasa et al. 2021). The p.Ile78Thr variant is reported at a frequency of 0.000144 in the East Asian population of the Genome Aggregation Database (version 2.1.1), but this frequency is based on only two alleles in a region of good sequencing coverage. Multiple in silico algorithms consistently predict a functional consequence of this variant, and carriers of this variant have been confirmed to have reduced G6PD enzyme activity (Dallol et al. 2012). Based on the available evidence, the p.Ile78Thr variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224890	SCV002506148	pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing	The G6PD c.143T>C; p.Ile48Thr variant (rs76645461), also known as G6PD Aures, is reported in the literature in multiple individuals affected with G6PD deficiency (Alfadhli 2005, Al-Jaouni 2011, Benmansour 2013, Nafa 1993). Individuals with this variant have reduced G6PD enzyme activity and is classified as a WHO Class III variant (Benmansour 2013). This variant is also reported in ClinVar (Variation ID: 10402) and is found in the East Asian population with an allele frequency of 0.01% (2/13861 alleles) in the Genome Aggregation Database. The isoleucine at codon 48 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.8). Based on available information, this variant is considered to be pathogenic. References: Alfadhli S et al. Molecular characterization of glucose-6-phosphate dehydrogenase gene defect in the Kuwaiti population. Arch Pathol Lab Med. 2005 Sep;129(9):1144-7. PMID: 16119988. Al-Jaouni SK et al. Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in Jeddah, Kingdom of Saudi Arabia. BMC Res Notes. 2011 Oct 24;4:436. PMID: 22018328. Benmansour I et al. Two new class III G6PD variants [G6PD Tunis (c.920A>C: p.307Gln>Pro) and G6PD Nefza (c.968T>C: p.323 Leu>Pro)] and overview of the spectrum of mutations in Tunisia. Blood Cells Mol Dis. 2013 Feb;50(2):110-4. PMID: 22963789. Nafa K et al. G6PD Aures: a new mutation (48 Ile-->Thr) causing mild G6PD deficiency is associated with favism. Hum Mol Genet. 1993 Jan;2(1):81-2. PMID: 8490627.
Dunham Lab, University of Washington	RCV000704108	SCV002599318	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in unrelated hemizygotes with deficiency, some with anemia and jaundice (PP4, PS4_M). Decreased activity in red blood cells (3-35%) (PS3). In silico analysis supports that this missense variant has a deleterious effect (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.997 (odds of pathogenicity 3155, Prior_P 0.1).
Fulgent Genetics, Fulgent Genetics	RCV002482854	SCV002788373	likely pathogenic	Malaria, susceptibility to; Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2021-11-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466850	SCV004195384	pathogenic	Malaria, susceptibility to	2024-03-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000704108	SCV004805193	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-03-17	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001796957	SCV005186094	pathogenic	G6PD deficiency	2024-05-29	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.233T>C (p.Ile78Thr) results in a non-conservative amino acid change located in the glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183351 control chromosomes. c.233T>C has been reported in the literature in the homozygous and hemizygous states in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. Nafa_1993, Dallol_2012, Al-Jaouni_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant results in 7% G6PD activity compared to WT in patient red blood cells (e.g. Nafa_1993). This variant is also known as c.143T>C(p.Ile48Thr) and G6PD Aures. The following publications have been ascertained in the context of this evaluation (PMID: 22018328, 23006493, 8490627). ClinVar contains an entry for this variant (Variation ID: 10402). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000011145	SCV000031372	other	G6PD AURES	2013-04-18	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000704108	SCV001132842	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2019-01-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748514	SCV005362980	likely pathogenic	G6PD-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The G6PD c.143T>C variant is predicted to result in the amino acid substitution p.Ile48Thr. This variant, also referred to as G6PD Aures, has been reported in multiple individuals with glucose-6-phosphate dehydrogenase deficiency (Nafa et al. 1993. PubMed ID: 8490627; Doss et al. 2016. PubMed ID: 27853304). One male patient carrying this variant was reported to have G6PD activity of ~7% compared to wild type in whole blood (Nafa et al. 1993. PubMed ID: 8490627) and another report referred to the p.Ile48Thr as a mild allele (Doss et al. 2016. PubMed ID: 27853304). This variant is reported in 0.014% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic.