Submissions for variant NM_000402.4(G6PD):c.961G>A (p.Val321Met)

gnomAD frequency: 0.00010  dbSNP: rs137852327

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000757320	SCV000233009	pathogenic	not provided	2015-08-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000405688	SCV000482072	pathogenic	G6PD deficiency	2017-04-28	criteria provided, single submitter	clinical testing	The G6PD c.871G>A (p.Val291Met) variant, also referred to as c.961G>A (p.Val321Met), is well described in the literature as a common variant across several Asian populations and is often referred to as G6PD Viangchan or G6PD Jammu. The variant was first identified in an individual of Laotian ancestry with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Beutler et al. 1991) and has since been reported as the most common G6PD variant in the Thai and Cambodian populations: Nuchprayoon et al. (2002) identified the p.Val291Met variant in 43 of 76 Thai G6PD deficiency patients, while the variant was reported in a total of 74 of 81 Cambodian G6PD deficiency patients (Matsuoka et al. 2005; Louicharoen et al. 2005). Control data are not reported in these studies for the p.Val291Met variant, which is reported at a frequency of 0.00785 in the East Asian population of the 1000 Genomes Project. Boonyuen et al. (2016) expressed the p.Val291Met variant in E. coli and reported that the KM for glucose-6-phosphate was similar to that of the wild type protein, though the KM for NADP+ was 5-fold higher than wild type and the kcat showed a 10-fold reduction in catalytic efficiency for NADP+ catalysis. Additionally, the variant showed significantly reduced thermostability as compared to wild type. Based on the collective evidence, the p.Val291Met 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	RCV000180545	SCV000677920	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2017-06-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757320	SCV000885495	pathogenic	not provided	2021-12-23	criteria provided, single submitter	clinical testing	The G6PD c.871G>A; p.Val291Met variant (rs137852327), also known as G6PD Viangchan, is reported in the literature as a Class II pathogenic variant and is associated with a severe decrease in G6PD enzyme activity (Beutler 1994, Hue 2009, Louicharoen 2005, Matsuoka 2005, Nuchprayoon 2008, Nuchprayoon 2002, Peng 2015, Yusoff 2003). Functional analyses of the variant protein also show reduced enzymatic activity and decreased thermal stability (Boonyuen 2016, Gomez-Manzo 2016). This variant is reported in ClinVar (Variation ID: 10386). This variant is found predominantly in the East Asian population with an allele frequency of 0.25% (35/13,844 alleles, including one homozygote and 13 hemizygotes) in the Genome Aggregation Database. The valine at codon 291 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.94). Based on available information, this variant is considered to be pathogenic. References: Beutler E. G6PD deficiency. Blood. 1994 84:3613-3636. Boonyuen U et al. Detailed functional analysis of two clinical glucose-6-phosphate dehydrogenase (G6PD) variants, G6PDViangchan and G6PDViangchan+Mahidol: Decreased stability and catalytic efficiency contribute to the clinical phenotype. Mol Genet Metab. 2016 118:84-91. Gomez-Manzo S et al. Functional and Biochemical Characterization of Three Recombinant Human Glucose-6-Phosphate Dehydrogenase Mutants: Zacatecas, Vanua-Lava and Viangchan. Int J Mol Sci. 2016 17. Hue NT et al. Glucose-6-phosphate dehydrogenase (G6PD) mutations and haemoglobinuria syndrome in the Vietnamese population. Malar J. 2009 8:152. Louicharoen C et al. G6PD Viangchan (871G>A) is the most common G6PD-deficient variant in the Cambodian population. J Hum Genet. 2005 50:448-452. Matsuoka H et al. Glucose-6-phosphate dehydrogenase (G6PD) mutations in Cambodia: G6PD Viangchan (871G>A) is the most common variant in the Cambodian population. J Hum Genet. 2005 50:468-472. Nuchprayoon I et al. Glucose-6-phosphate dehydrogenase mutations in Mon and Burmese of southern Myanmar. J Hum Genet. 2008 53:48-54. 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 19:185. Peng Q et al. Large cohort screening of G6PD deficiency and the mutational spectrum in the Dongguan District in Southern China. PLoS One. 2015 10:e0120683. Yusoff NM et al. G6PD Viangchan and G6PD Mediterranean are the main variants in G6PD deficiency in the Malay population of Malaysia. Southeast Asian J Trop Med Public Health. 2003 34 Suppl 3:135-137.
Fulgent Genetics, Fulgent Genetics	RCV000763203	SCV000893822	pathogenic	Malaria, susceptibility to; Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2021-10-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000180545	SCV000951744	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 291 of the G6PD protein (p.Val291Met). This variant is present in population databases (rs137852327, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with G6PD deficiency (PMID: 15906717, 16155737, 18329300). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10386). 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%. Experimental studies have shown that this missense change affects G6PD function (PMID: 3338798, 27213370). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000180545	SCV000966815	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2017-06-19	criteria provided, single submitter	clinical testing	The p.Val321Met (NM_000402.3 c.961G>A) (also referred to as c.871G>A, p.Val291Me t on NM_001042351, G6PD Viangchan and G6PD Jammu) variant in G6PD is one of the most common variants associated with Glucose-6-phosphate dehydrogenase (G6PD) de ficiency in the Asian population and has been reported in several males (hemizyg ous) and females (heterozygous, compound heterozygous, and homozygous) with G6PD deficiency (Beutler 1991, Peng 2005, Ko 2006, Ninokata 2006, Li 2008, Nuchpray oon 2008, Natakomol 2013, Li 2015). It should be noted that most individuals rep orted with this variant were identified through screening by enzyme testing of a pparently healthy individuals at the time of the study. This variant has been re ported in ClinVar (Variation ID#10386) as a pathogenic variant. It has been ide ntified in 0.24% (33/13881) of East Asian chromosomes including 14 hemizygotes b y the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; db SNP rs137852327). In vitro functional studies provide evidence that the p.Val321 Met variant may impact protein function (Boonyuen 2016 and Gomez-Manzo 2016). In summary, although additional studies are required to fully establish its clinic al significance, this variant is likely pathogenic for G6PD deficiency in an X-l inked manner based upon its occurrence in individuals with this disorder and da ta from functional studies.
Centogene AG - the Rare Disease Company	RCV001250220	SCV001424422	pathogenic	G6PD deficient hemolytic anemia		criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000180545	SCV001443091	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency		criteria provided, single submitter	clinical testing	This variant in exon 9 of the G6PD gene results in the amino acid substitution from Valine to Methionine at codon 321 (p.Val321Met) with the sequence change of c.961G>A (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at Lifecell diagnostics. The variant was first identified with glucose-6-phosphate dehydrogenase ( G6PD) deficiency in a person of Laotian ancestry (Beutler et al . 1991) and has since been recorded as the most common variant of G6PD in the Thai and Cambodian populations. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. The Missense Variants Z-Score for this variant is 2.60. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. The G6PD c.961G>A; p.Val321Met variant, also referred to as c.871G>A; p.Val291Met, commonly known as G6PD Viangchan, has been described in the literature as a Class II to Class III pathogenic variant and is associated with a moderate to severe decrease in enzyme activity (Hue et al., 2009; PMID: 19589177, Nuchprayoon et al., 2002; PMID: 11793482). This variant is one of the most common variants associated with Glucose-6-phosphate dehydrogenase (G6PD) deficiency in the Asian population (Beutler et al.,1991; PMID: 1805484, Peng et al., 2005; PMID: 25775246, Ko et al., 2006; PMID: 16777444, Ninokata et al., 2006; PMID: 16528451, Li et al., 2008; PMID: 18329300, Nuchprayoon et al., 2008; PMID: 18046504, Nantakomol et al., 2013; PMID: 23965028, Li et al., 2015; PMID: 26226515). Experimental studies have shown that this missense change impairs G6PD enzyme activity in vitro (Gomez-Manzo et al., 2016; PMID: 27213370 and Boonyuen 2016 et al., PMID: 27053284).
Ambry Genetics	RCV001266092	SCV001444264	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000757320	SCV001874266	pathogenic	not provided	2022-05-31	criteria provided, single submitter	clinical testing	Reported to be a common pathogenic variant in Southeast Asian populations (Nuchprayoon et al., 2002); Published functional studies demonstrate that this variant is associated with lower catalytic constant and catalytic efficiency (Gomez-Manzo et al., 2016); This variant is associated with the following publications: (PMID: 30315739, 26226515, 25775246, 29702993, 30609409, 27053284, 11793482, 29783823, 25536053, 30161219, 3338798, 16136268, 29339739, 11499668, 12850494, 25440321, 23313052, 18329300, 16777444, 1805484, 16155737, 31180159, 34272389, 33072997, 27213370, 31589614, 33083013, 12215013, 27535533)
Revvity Omics, Revvity	RCV000180545	SCV002023786	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-07-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000180545	SCV002516413	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000757320	SCV002573775	pathogenic	not provided	2021-10-18	criteria provided, single submitter	clinical testing	PM1, PS3, PS4
MGZ Medical Genetics Center	RCV000180545	SCV002580614	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-01-10	criteria provided, single submitter	clinical testing
Dunham Lab, University of Washington	RCV000180545	SCV002599349	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, favism, and jaundice (PS4_M, PP4). Decreased activity in red blood cells (0-29%) (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 0.997 (odds of pathogenicity 3155, Prior_P 0.1).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000180545	SCV003922000	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2021-05-06	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 valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (23 heterozygotes, 1 homozygote, 16 hemizygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is reported as a common pathogenic variant in the Asian population, also referred to as G6PD Viangchan or G6PD Jammu (ClinVar, PMID: 11793482, 33051526). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000757320	SCV004011706	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	G6PD: PS3, PS4, PM2
Baylor Genetics	RCV003460452	SCV004195381	pathogenic	Malaria, susceptibility to	2024-03-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000405688	SCV004803748	pathogenic	G6PD deficiency	2024-01-25	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.961G>A (p.Val321Met, also known as G6PD Viangchan) results in a conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal (IPR022675) 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 0.00022 in 182854 control chromosomes, predominantly at a frequency of 0.0025 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.00022 vs 0.29), allowing no conclusion about variant significance. c.961G>A has been reported in the literature in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency and has been reported to be a common pathogenic variant in Southeast Asian population (example, Nuchprayoon_2002, Poon_1988). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 40%-50% of catalytic activity of normal G6PD activities in vitro (Boonyuen_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28583873, 11793482, 3338798). ClinVar contains an entry for this variant (Variation ID: 10386). Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000757320	SCV005196685	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000011116	SCV000031343	other	G6PD VIANGCHAN	2017-05-24	no assertion criteria provided	literature only
OMIM	RCV000011117	SCV000031344	other	G6PD JAMMU	2017-05-24	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004748513	SCV005364206	pathogenic	G6PD-related disorder	2024-07-14	no assertion criteria provided	clinical testing	The G6PD c.871G>A variant is predicted to result in the amino acid substitution p.Val291Met. This variant, also referred to as G6PD Viangchan/Jammu, has previously been reported to be causative for Glucose-6-Phosphate Dehydrogenase Deficiency. This variant is probably the most common causative variant in non-Chinese Southeast Asian population (Nuchprayoon et al. 2008. PubMed ID: 18046504; Boonyuen et al. 2016. PubMed ID: 27053284). This variant is reported in 0.25% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.