Submissions for variant NM_000402.4(G6PD):c.1268G>A (p.Arg423His)

dbSNP: rs137852316

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756196	SCV000883925	pathogenic	not specified	2019-03-20	criteria provided, single submitter	clinical testing	The G6PD c.1178G>A; p.Arg393His variant (rs137852316), also known as G6PD Nashville and G6PD Anaheim, has been reported in the literature in individuals and families with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Beutler 1991, Filosa 1992). This variant is reported as pathogenic in ClinVar (Variation ID: 10370) and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1177C>G; p.Arg393Gly) have been reported in individuals with G6PD deficiency and is considered pathogenic (Beutler 1995). The arginine at codon 393 is highly conserved and computation algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be deleterious. Further, functional analyses demonstrate protein instability and impairment (Gomez-Manzo 2014, Wang 2006, Wang 2009). Based on the above information, this variant is considered pathogenic. References: Beutler E et al. DNA sequence abnormalities of human glucose-6-phosphate dehydrogenase variants. J Biol Chem. 1991 Mar 5;266(7):4145-50. Beutler E et al. Three new exon 10 glucose-6-phosphate dehydrogenase mutations. Blood Cells Mol Dis. 1995;21(1):64-72. Filosa S et al. Molecular basis of chronic non-spherocytic haemolytic anaemia: a new G6PD variant (393 Arg----His) with abnormal KmG6P and marked in vivo instability. Br J Haematol. 1992 Jan;80(1):111-6. Gomez-Manzo S et al. The Stability of G6PD Is Affected by Mutations with Different Clinical Phenotypes. Int J Mol Sci. 2014 Nov; 15(11): 21179-21201. Wang X et al. Functional properties of two mutants of human glucose 6-phosphate dehydrogenase, R393G and R393H, corresponding to the clinical variants G6PD Wisconsin and Nashville. Biochim Biophys Acta. 2006;1762(8):767-774. Wang X et al. Clinical mutants of human glucose 6-phosphate dehydrogenase: Impairment of NADP+ binding affects both folding and stability. Biochim Biophys Acta. 2009;1792(8):804-809.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000066231	SCV002118158	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2021-05-07	criteria provided, single submitter	clinical testing	Experimental studies have shown that this variant affects G6PD protein function (PMID: 16934959, 19465117, 25407525). For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function. This variant has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 1999409, 1536798). ClinVar contains an entry for this variant (Variation ID: 10370). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 393 of the G6PD protein (p.Arg393His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.
Dunham Lab, University of Washington	RCV000066231	SCV002599367	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in unrelated hemizygotes with deficiency, acute anemia, and CNSHA (PS4_M, PP4). In one family, heizygous brothers both have deficiency and acute or chronic anemia (PP1). Decreased activity in red blood cells (1-33%) (PS3). Within dimer interface (PM1). Predicted to be deleterious by SIFT, Polyphen, and MutationTaster (PP3). Not found in gnomAD (PM2). Reported as pathogenic by Invitae and ARUP Laboratories (PP5). Post_P 0.9997 (odds of pathogenicity 28416, Prior_P 0.1).
Revvity Omics, Revvity	RCV000066231	SCV003820110	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-04-11	criteria provided, single submitter	clinical testing
3billion	RCV000066231	SCV004013754	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 1536798, 16934959, 19224086, 25407525). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010370 / PMID: 1999409). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 1536798, 1999409). Different missense changes at the same codon (p.Arg393Cys, p.Arg393Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001066811, VCV001722672 / PMID: 7655862). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Mayo Clinic Laboratories, Mayo Clinic	RCV003480028	SCV004225521	pathogenic	not provided	2023-02-20	criteria provided, single submitter	clinical testing	PP3, PP5, PM2, PS3, PS4_moderate
OMIM	RCV000011090	SCV000031317	other	G6PD PORTICI	1992-01-01	no assertion criteria provided	literature only
OMIM	RCV000030890	SCV000031340	other	G6PD NASHVILLE	1990-12-01	no assertion criteria provided	literature only
OMIM	RCV000030891	SCV000031341	other	G6PD ANAHEIM	1990-12-01	no assertion criteria provided	literature only
OMIM	RCV000066231	SCV005374535	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	1992-01-01	no assertion criteria provided	literature only