Submissions for variant NM_000402.4(G6PD):c.1466G>T (p.Arg489Leu)

gnomAD frequency: 0.00046  dbSNP: rs72554665

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000756195	SCV000225548	pathogenic	not provided	2015-11-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000375428	SCV000482066	pathogenic	G6PD deficiency	2019-04-05	criteria provided, single submitter	clinical testing	The G6PD c.1376G>T (p.Arg459Leu) missense variant, also described as G6PD Canton, is one of the most common glucose-6-phosphate dehydrogenase (G6PD) deficiency variants in certain Asian populations. Across a selection of the available literature, the p.Arg459Leu variant was observed in 116 G6PD deficiency cases, mostly in individuals of Chinese ancestry (Stevens et al. 1990; Tang et al. 1992; Cai et al. 2000; Deng et al. 2007; Phompradit et al. 2011; Yang et al. 2014). Control data are unavailable for the p.Arg459Leu variant, which is reported at a frequency of 0.01061 in the East Asian population of the Genome Aggregation Database including 42 hemizygotes in this population and 43 hemizygotes in the total population. Based on the evidence, the p.Arg459Leu variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl	RCV000174272	SCV000677945	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2015-06-06	criteria provided, single submitter	clinical testing
Invitae	RCV000174272	SCV000768476	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 459 of the G6PD protein (p.Arg459Leu). This variant is present in population databases (rs72554665, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with glucose-6-phosphate deficiency (PMID: 1562739, 2263506, 6714986, 8537082, 10643148, 11499668, 17726510, 20203002, 21446359, 25541721, 25775246, 26823837). It has also been observed to segregate with disease in related individuals. This variant is also known as Canton variant. ClinVar contains an entry for this variant (Variation ID: 100058). 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: 16607506). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756195	SCV000883924	pathogenic	not provided	2021-11-02	criteria provided, single submitter	clinical testing	The G6PD c.1376G>T; p.Arg459Leu variant (rs72554665) is reported in the literature in the hemizygous, homozygous, and compound heterozygous states in individuals of East Asian descent affected with G6PD deficiency (Fu 2018, Stevens 1990, Tang 1992). Individuals carrying this variant have been shown to have G6PD enzymatic activity lower than levels found in the general Chinese population (Tang 1992) and this variant has been reported in 27.5% of positive newborn screens for G6PD deficiency in Guangxi, China (Fu 2018). The variant is reported in ClinVar (Variation ID: 100058), and it is found in the East Asian population with an overall allele frequency of 1.1% (157/14796 alleles with 42 hemizygotes) in the Genome Aggregation Database. The arginine at codon 459 is moderately conserved and is located in the dehydrogenase domain. Additionally, another missense variant at the same amino acid (p.Arg459Pro) has been observed in individuals with G6PD deficiency and is considered pathogenic (Calabro 1993). Based on available information, the p.Arg459Leu variant is considered to be pathogenic. References: Calabro V et al. Genetic heterogeneity of glucose-6-phosphate dehydrogenase deficiency revealed by single-strand conformation and sequence analysis. Am J Hum Genet. 1993 Mar;52(3):527-36. 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. Stevens D et al. G6PD Canton a common deficient variant in South East Asia caused by a 459 Arg----Leu mutation. Nucleic Acids Res. 1990: 18(23):7190. Tang T et al. Diverse point mutations result in glucose-6-phosphate dehydrogenase (G6PD) polymorphism in Taiwan. Blood. 1992: 79(8):2135-40.
Revvity Omics, Revvity	RCV000174272	SCV002023782	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-12-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000174272	SCV002516409	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Dunham Lab, University of Washington	RCV000174272	SCV002599395	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 kernicterus (PS4_M, PP4). Segregates with deficiency in multiple unrelated families (PP1). Decreased activity in red blood cells (1-52%) (PS3). Affects same amino acid as pathogenic 459R>P (ClinVar ID 10422) (PM5). Predicted to be disease causing by Mutation Taster and possibly damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.9997 (odds of pathogenicity 28416, Prior_P 0.1).
Fulgent Genetics, Fulgent Genetics	RCV002498469	SCV002810419	pathogenic	Malaria, susceptibility to; Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-03-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000756195	SCV003929741	pathogenic	not provided	2023-06-04	criteria provided, single submitter	clinical testing	In vitro functional studies indicate that R459L has a reduced catalytic efficiency of approximately 50% compared to wild type enzyme (Boonyuen et al., 2017); 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: 9891846, 34659341, 34746046, 2263506, 11499668, 14505231, 1953767, 29783823, 29339739, 11793482, 31374327, 34570182, 12215013, 34953813, 29251006, 35193651, 28376293, 35313968, 8571933, 28583873)
Baylor Genetics	RCV003460788	SCV004195383	pathogenic	Malaria, susceptibility to	2023-10-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000756195	SCV004225510	pathogenic	not provided	2022-10-20	criteria provided, single submitter	clinical testing	PP4, PP5, PM5, PS3, PS4_moderate
OMIM	RCV000011104	SCV000031331	other	G6PD CANTON	2017-05-24	no assertion criteria provided	literature only
OMIM	RCV000011105	SCV000031332	other	G6PD GIFU	2017-05-24	no assertion criteria provided	literature only
OMIM	RCV000011106	SCV000031333	other	G6PD AGRIGENTO	2017-05-24	no assertion criteria provided	literature only
OMIM	RCV000011107	SCV000031334	other	G6PD TAIWAN-HAKKA	2017-05-24	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000375428	SCV001142504	pathogenic	G6PD deficiency	2020-01-06	no assertion criteria provided	curation	NM_001042351.1:c.1376G>T in the G6PD gene has an allele frequency of 0.012 in East Asian subpopulation in the gnomAD database. The c.1376G>T (p.Arg459Leu) variant was observed in numerous G6PD deficiency cases, mostly in individuals of Chinese ancestry (PMID: 25440321; 22171972; 21874587). Experimental studies have shown that this missense change causes a significant reduction in enzyme activity and affinity for glucose-6-phosphate (PMID: 16607506). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, FATHMM-MKL, MVP, MutationTaster and REVEL. ACMG/AMP Criteria applied: PS3; PS4; PP4; PP3.