Submissions for variant NM_000402.4(G6PD):c.1478G>A (p.Arg493His)

gnomAD frequency: 0.00012  dbSNP: rs72554664

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174271	SCV000225547	pathogenic	not provided	2013-05-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000174271	SCV000603772	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing	The G6PD c.1388G>A; p.Arg463His variant (rs72554664), also known as G6PD Kaiping, is reported in the literature as a common G6PD deficiency variant in Asian populations (Chiu 1991, Fu 2018, Li 1998, Nuchprayoon 2002). This variant is reported in ClinVar (Variation ID: 100059), and is found in the East Asian population with an allele frequency of 0.70% (104/14782 alleles, including 32 hemizygotes and a single homozygote) in the Genome Aggregation Database. The arginine at codon 463 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.1387C>T; p.Arg463Cys, c.1387C>A; p.Arg462Ser) have been reported in individuals with G6PD deficiency (Hirono 1997, Rodrigues 2002). Based on available information, the p.Arg463His variant is considered to be pathogenic. References: Chiu DT et al. Two commonly occurring nucleotide base substitutions in Chinese G6PD variants. Biochem Biophys Res Commun. 1991 180(2):988-93. Fu C et al. Newborn screening of glucose-6-phosphate dehydrogenase deficiency in Guangxi, China: determination of optimal cutoff value to identify heterozygous female neonates. Sci Rep. 2018 Jan 16;8(1):833. Hirono A et al. Molecular analysis of eight biochemically unique glucose-6-phosphate dehydrogenase variants found in Japan. Blood. 1997 Jun 15;89(12):4624-7. Li P et al. Analysis of common mutations and associated haplotypes in Chinese patients with glucose-6-phosphate dehydrogenase deficiency. Biochem Mol Biol Int. 1998 46(6):1135-43. Nuchprayoon I et al. Glucose-6-phosphate dehydrogenase (G6PD) mutations in Thailand: G6PD Viangchan (871G>A) is the most common deficiency variant in the Thai population. Hum Mutat. 2002 Feb;19(2):185. Rodrigues MO et al. Glucose-6-phosphate dehydrogenase deficiency in Portugal: biochemical and mutational profiles, heterogeneity, and haplotype association. Blood Cells Mol Dis. 2002 Mar-Apr;28(2):249-59.
Fulgent Genetics, Fulgent Genetics	RCV000763201	SCV000893820	pathogenic	Malaria, susceptibility to; Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000823393	SCV000964252	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 463 of the G6PD protein (p.Arg463His). This variant is present in population databases (rs72554664, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This variant has been described as a common cause of glucose-6-phosphate dehydrogenase deficiency in southeast Asia, although it has also been reported in affected individuals from other populations (PMID: 9589612, 30315739, 17726510, 21446359, 15906717, 15223006, 20236109). This variant is also known as Kaiping. ClinVar contains an entry for this variant (Variation ID: 100059). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266661	SCV001444838	pathogenic	Inborn genetic diseases	2016-06-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000174271	SCV001962678	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	G6PD: PS3, PM1, PP1:Moderate, PP3, PS4:Supporting
GeneDx	RCV000174271	SCV001982609	pathogenic	not provided	2023-09-05	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: 15625830, 8935319, 23313052, 25440321, 20236109, 7390473, 29783823, 15766741, 7327562, 18270558, 11793482, 12497642, 15316963, 18046504, 34659341, 21931771, 29339739, 18329300, 24958328, 25775246, 26829728, 29702993, 29783822, 15223006, 17587269, 23006493, 15727905, 21874587, 16155737, 16331553, 16528451, 15476167, 17018380, 16513531, 16329560, 11295127, 16927025, 22938511, 14505231, 1953767, 9891846, 28376293, 31628766, 33069889, 32959227, 34953813, 36071769, 35611242, 29251006, 35193651, 35313968, 12215013, 34272389)
Revvity Omics, Revvity	RCV000823393	SCV002023787	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-01-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000823393	SCV002516408	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000823393	SCV002557889	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with G6PD deficient hemolytic anemia (favism) (MIM#300908). (I) 0109 - This gene is associated with X-linked recessive disease. Hemizygous males and homozygous females are commonly affected, however some heterozygous female carriers can also be affected depending on X inactivation. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (71 heterozygotes, 1 homozygote, 33 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (0 heterozygotes, 0 homozygotes, 1 hemizygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glucose-6-phosphate dehydrogenase, C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as the Kaiping variant, it is one the most common pathogenic alleles amongst the Chinese population; and is classified as a WHO class II variant (severe deficiency) (PMID: 33051526). In addition, it is consistently classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1207 - Parental origin of the variant is unresolved (duo analysis, father not tested). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Dunham Lab, University of Washington	RCV000823393	SCV002599397	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, jaundice, and favism, and one with CNSHA (PS4_M, PP4). Segregates with deficiency in a family (PP1). Decreased activity in red blood cells (1-44%) and when expressed in E. coli (PS3). Predicted to be disease causing by Mutation Taster and probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.999 (odds of pathogenicity 6563, Prior_P 0.1).
Illumina Laboratory Services, Illumina	RCV000991190	SCV004014652	pathogenic	G6PD deficiency	2023-04-25	criteria provided, single submitter	clinical testing	The G6PD c.1478G>A (p.Arg493His) variant, also known as c.1388G>A (p.Arg463His), or G6PD Kaiping, is a missense variant. In the literature, this variant is reported as one of the most common pathogenic variants associated with glucose-6-phosphate dehydrogenase deficiency in the East Asian population (PMID: 36949502; 33051526). The highest frequency of this allele in the Genome Aggregation Database is 0.007036 in the East Asian population (version 2.1.1). This frequency is high but is consistent with disease prevalence estimates. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant has been classified as pathogenic by at least twelve submitters in ClinVar. Based on the available evidence, the c.1478G>A (p.Arg493His) variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency.
Baylor Genetics	RCV003460789	SCV004195386	pathogenic	Malaria, susceptibility to	2024-03-26	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000823393	SCV004812458	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-04	criteria provided, single submitter	clinical testing	This sequence change in G6PD is predicted to replace arginine with histidine at codon 463, p.(Arg463His). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the C-terminal glucose-6-phosphate dehydrogenase domain. There is a small physicochemical difference between arginine and histidine. The highest population minor allele frequency in gnomAD v2.1 is 0.7% (104/14,782 alleles, 1 homozygote, 32 hemizygotes) in the East Asian population. This variant is the most common cause of glucose-6-phosphate dehydrogenase (G6PD) deficiency in China (also known as Kaiping). It has been detected in hemizygous in affected males and compound heterozygous with a second pathogenic variant or homozygous in affected females. Individuals with this variant display reduced G6PD activity in their cells, with female heterozygous carriers demonstrating moderate deficiency (PMID: 33051526). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP3, PP4.
OMIM	RCV000011120	SCV000031347	other	G6PD KAIPING	2017-05-24	no assertion criteria provided	literature only
OMIM	RCV000011121	SCV000031348	other	G6PD ANANT	2017-05-24	no assertion criteria provided	literature only
OMIM	RCV000011122	SCV000031349	other	G6PD DHON	2017-05-24	no assertion criteria provided	literature only
OMIM	RCV000011123	SCV000031350	other	G6PD PETRICH-LIKE	2017-05-24	no assertion criteria provided	literature only
OMIM	RCV000011124	SCV000031351	other	G6PD SAPPORO-LIKE	2017-05-24	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000991190	SCV001142503	pathogenic	G6PD deficiency	2020-01-06	no assertion criteria provided	curation	NM_001042351.1:c.1388G>A in the G6PD gene has an allele frequency of 0.007 in East Asian subpopulation in the gnomAD database. This variant has been described as a common cause of glucose-6-phosphate dehydrogenase deficiency in Southeast Asia, although it has also been reported in affected individuals from other populations (PMID: 9589612, 30315739, 17726510, 21446359, 15906717, 15223006, 20236109). Experimental studies have shown that this missense change causes a significant reduction in enzyme activity and affinity for glucose-6-phosphate (PMID: 16607506). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFTT. aken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PS4; PP4.