Submissions for variant NM_000402.4(G6PD):c.292G>A (p.Val98Met)

gnomAD frequency: 0.03616  dbSNP: rs1050828

Total submissions: 37

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000224469	SCV000111283	pathogenic	not provided	2017-03-29	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224469	SCV000280908	pathogenic	not provided	2015-08-24	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000079404	SCV000494242	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2016-06-28	criteria provided, single submitter	clinical testing	The c.202G>A (p.Val68Met) missense variant is recognized as a disease-causing variant in the G6PD gene. Functional studies demonstrate reduced enzymatic activity of the G allele compared to WT. The prevalence of the variant in affected individuals (homozygous) is increased compared with the prevalence in controls and there is familial co-segregation with disease (Bwayo et al. 2013; Manjurano et al. 2012; Maiga et al. 2014; Shah et al. 2014; Pisani et al. 2012; Vulliamy et al. 1988; Odievre et al. 2011). Although the frequency of this variant in the African population within ExAC (http://exac.broadinstitute.org) is high it is consistent with observed and expected based on disease incidence (11.34%). Computational algorithms predict the variant has a damaging or deleterious effect. This variant is has been classified as pathogenic by multiple reputable clinical testing laboratories (Emory, Division of Human Genetics at Children’s Hospital of Philadelphia). In summary, this variant c.202G>A (p.Val68Met) meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing.
GeneDx	RCV000224469	SCV000577149	pathogenic	not provided	2022-02-23	criteria provided, single submitter	clinical testing	Results in 10-23% of normal G6PD activity and causes acute hemolytic anemia triggered by infections, certain drugs, and fava beans (Vulliamy et al., 1988; Beutler et al., 1989; Shah et al., 2014); This variant is associated with the following publications: (PMID: 12524354, 24943486, 21153663, 1889820, 22307442, 21931771, 8733135, 25182376, 23144702, 2836867, 11852882, 21479984, 25201310, 27884173, 2572288, 27853304, 28512736, 30609409, 31564435, 32387609, 1303173, 30577886, 31980526, 32641076, 33587123, 3393536, 34272389, 33069889, 33072997)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999820	SCV000603770	pathogenic	not specified	2018-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV000079404	SCV000647800	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2018-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine with methionine at codon 68 of the G6PD protein (p.Val68Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs1050828, ExAC 11%). ClinVar contains an entry for this variant (Variation ID: 37123).  This variant is also known as the Asashi variant or p.Val98Met in the literature. This variant frequently co-occurs with the c.376A>G (p.Asn126Asp) variant (rs1050829) in cis (on the same chromosome), which is known as the G6PD A- haplotype c.[202G>A; 376A>G] . The G6PD A- haplotype is the most prevalent G6PD deficiency variant in African populations which is present at 0.2% (PMID: 1303173, 24505519, 2572288, 4359638). ClinVar contains an entry for the G6PD A- haplotype (Variation ID: 10361). This variant has been reported to co-occur with another G6PD variant independent of the A- haplotype in a Japanese family affected with G6PD deficiency (PMID: 11852882). It has also been identified as homozygous independent of the A- haplotype in individuals suspected with G6PD deficiency (PMID: 23006493). While this variant alone has been shown to only mildly affect enzyme activity, the c.[202G>A; 376A>G] changes of the G6PD A- haplotype have been reported to act synergistically to cause dramatic reduction of the stability and enzymatic activity of the G6PD protein (PMID: 3393536, 1303173, 10734064, 6015571, 2836867, 16356170). For these reasons, this variant on the c.[202G>A; 376A>G] haplotype has been classified as Pathogenic.
Counsyl	RCV000079404	SCV000677948	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2015-10-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000079404	SCV000711717	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-12-26	criteria provided, single submitter	clinical testing	The p.Val98Met variant in G6PD (frequently reported as p.Val68Met on transcript NM_001042351.1) is a well-established pathogenic variant for glucose-6-phosphate dehydrogenase deficiency (G6PD) and has been shown to alter G6PD enzyme activity (Pal 2017 PMID: 28512736, Hirono 2002 PMID: 11852882, Hirono 1988 PMID: 2836867, Shah 2014 PMID: 25201310, Odièvre 2011 PMID: 21479984). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 37123) and has been identified in 11.6% (3560/30745) of African chromosomes, including 155 female homozygotes and 995 male hemizygotes, by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). The variant's high frequency is consistent with the prevalence of G6PD deficiency in African populations and is thought to be a result of a partial protection against malaria (Manjurano 2012 PMID: 23144702, Luzzatto 2016 PMID: 27040960). Computational prediction tools and conservation analysis are consistent with pathogenicity. Of note, this variant frequently co-occurs with the p.Asn156Asp in cis and is known as the G6PD A-allele, which is a class III variant with a moderate level of deficiency (10-60% activity). In summary, this variant meets criteria to be classified as pathogenic for X-linked G6PD deficiency. ACMG/AMP Criteria applied: PS4_VeryStrong, PS3_Moderate, PP3.
Mendelics	RCV000079404	SCV001142114	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2019-05-28	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001095679	SCV001251452	pathogenic	G6PD deficiency; Anemia, nonspherocytic hemolytic, due to G6PD deficiency		criteria provided, single submitter	research	G6PD c.292G>A (p.V98M) and c.466A>G (p.N156D), often occur together in cis as part of a haplotype, referred to as the enzyme variant A- (PMID: 5448; 1303173). This variant is associated with glucose-6-phosphate dehydrogenase deficiency.
Ambry Genetics	RCV001267358	SCV001445539	pathogenic	Inborn genetic diseases	2023-11-20	criteria provided, single submitter	clinical testing	The c.[202G>A;376A>G] (p.[V68M;N126D]) complex allele affects exon 4 (coding exon 3) and exon 5 (coding exon 4) of the G6PD gene. This alteration results from a G to A substitution at nucleotide position 202, causing the valine (V) at amino acid position 68 to be replaced by a methionine (M), and from an A to G substitution at nucleotide position 376, causing the asparagine (N) at amino acid position 126 to be replaced by an aspartic acid (D). Based on data from the Genome Aggregation Database (gnomAD), the G6PD c.202G>A alteration was observed in 1.2% (2365/205030) total alleles studied, with a frequency of 11.6% (2208/18968) African alleles, including 89 homozygotes and 599 hemizygotes; the G6PD c.376A>G alteration was observed in 3.2% (6586/205081) total alleles studied, with a frequency of 31.8% (6025/18923) African alleles, including 714 homozygotes and 1605 hemizygotes. The G6PD c.[202G>A;376A>G] complex allele is also known as the “A-" haplotype and it is the most common G6PD deficiency disease-causing allele in African populations. Of note, the c.376A>G (p.N126D) alteration is considered a benign variant when seen in isolation (Town, 1992; Shahjahani, 2013). A significant reduction in enzyme stability and activity has been observed when the c.202G>A (p.V68M) and c.376A>G (p.N126D) variants are present in cis (on the same chromosome) (Vulliamy, 1998; Town, 1992; Gómez-Gallego, 2000). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000079404	SCV001482573	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-03-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000224469	SCV001715690	pathogenic	not provided	2023-05-19	criteria provided, single submitter	clinical testing	PS3, PS4
CeGaT Center for Human Genetics Tuebingen	RCV000224469	SCV001962681	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	G6PD: PP1:Strong, PM1, PS4:Moderate, PP4, PS3:Supporting
Illumina Laboratory Services, Illumina	RCV000606259	SCV002034762	pathogenic	G6PD deficiency	2021-11-11	criteria provided, single submitter	clinical testing	The G6PD c.292G>A (p.Val98Met) variant, which is also called c.202G>A (p.Val68Met), is a missense variant that has a well-characterized role in glucose-6-phosphate dehydrogenase (G6PD) deficiency, accounting for up to 25% of cases in sub-Saharan Africa. This variant has been reported in a large number of individuals with G6PD deficiency, including in a heterozygous, hemizygous, and homozygous state (Vulliamy et al. 1991; McDade et al. 2008; Tine et al. 2012; Dallol et al. 2012; Shah et al. 2014). It is commonly found in cis with the c.466A>G (p.Asn156Asp) variant, which is also known as c.376A>G (p.Asn126Asp), and this complex allele is often referred to as the A-(1) allele. The p.Val98Met variant is reported at a frequency of 0.116400 in the African/African American population of the Genome Aggregation Database (version 2.1.1), including in 90 homozygotes and 641 hemizygotes. This frequency is high but consistent with the prevalence of G6PD deficiency in this region and the potentially limited clinical expression of G6PD deficiency. Reduced enzyme activity of approximately 40% for heterozygotes and 80% for hemizygotes and homozygotes in red blood cells from individuals who carry the p.Val98Met variant only has been observed (Hirono et al. 2002; Shah et al. 2014). Based on the collective evidence, the p.Val98Met variant, is classified as pathogenic for G6PD deficiency.
Centogene AG - the Rare Disease Company	RCV000079404	SCV002059871	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2021-11-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000079404	SCV002072536	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-01-12	criteria provided, single submitter	clinical testing	This variant was identifiedas hemizygous and togehter with NM_001042351.3:c.376A>G._x000D_ Criteria applied: PS4, PS3_SUP, PP3
AiLife Diagnostics, AiLife Diagnostics	RCV000224469	SCV002503173	pathogenic	not provided	2021-07-02	criteria provided, single submitter	clinical testing
Dunham Lab, University of Washington	RCV000079404	SCV002599322	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in three unrelated families, where hemizygotes present with deficiency, some with hyperbilirubinemia, jaundice, and anemia (PS4_M, PP4). Two son-and-mother pairs both have variant and decreased activity, and sons have additional symptoms (PP1). Decreased activity in red blood cells (3-71%) and when expressed in E. coli (PS3). Predicted to be damaging by SIFT and probably damaging by PolyPhen (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.994 (odds of pathogenicity 1516, Prior_P 0.1).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000079404	SCV003806742	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-12-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PP3 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000606259	SCV003844610	pathogenic	G6PD deficiency	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.292G>A (p.Val98Met) results in a conservative amino acid change located in the NAD-binding domain (IPR022674) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0091 in 183313 control chromosomes, predominantly at a frequency of 0.12 within the African or African-American subpopulation in the gnomAD database, including 59 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.0091 vs 0.29), and is consistent with the prevalence of G6PD deficiency in this region. Therefore, this allows no strong conclusion about variant significance. This variant is commonly observed as a complex variant (referred to as the A- haplotype) in cis with c.466A>G, p.Asn156Asp in individuals with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. Dallol_2012, Shah_2014). c.292G>A has also been reported as a single variant, independent from the A- haplotype, in the literature in the hemizygous, homozygous, and heterozygous state in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency, including at least two unrelated cases of an affected hemizygous male with an affected heterozygous mother (e.g. Hirono_2002, Dallol_2012, Warang_2017, Powers_2018, Chen_2018). These data indicate that the variant is very likely to be associated with disease. Publications have reported experimental evidence evaluating an impact on protein function (e.g. Town_1992, Shah_2014). The most pronounced variant effect results in an approximately 40% reduction in enzyme activity for heterozygotes, and 80% for hemizygotes and homozygotes. Furthermore, this variant has been given a WHO classification of Class III: mild to moderate enzyme deficiency (10-60% residual activity). Twenty-three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority have classified the variant as pathogenic (n=19)/likely pathogenic (n=2), and two classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000224469	SCV004026486	pathogenic	not provided	2022-06-23	criteria provided, single submitter	clinical testing	PS4, PP3, PP2, PS3
Baylor Genetics	RCV003460495	SCV004195377	pathogenic	Malaria, susceptibility to	2024-03-30	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000079404	SCV004239032	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-12-08	criteria provided, single submitter	clinical testing	While G6PD c.202G>A in isolation (called Asahi variant) has occasionally been identified in individuals with G6PD deficiency, it has more commonly been reported to co-occur on the same haplotype with another variant c.376A>G; p.Asn126Asp (complex variant c.376A>G/c.202G>A is called A- variant) and this complex variant has also been observed in individuals with G6PD deficiency. However, G6PD c.376A>G in isolation is considered a non-deficient variant that does not cause disease, and has instead been shown to act as a genetic modifier, increasing the risk of G6PD deficiency by two-fold in individuals heterozygous for c.202G>A3. Functional studies support that the A- variant results in clinically significant G6PD enzyme deficiency. c.202G>A (rs1050828) is present in a large population dataset (gnomAD v2.1.1: 2365/205030 total alleles; 1.2%; 641 hemizygotes and 90 homozygotes), and has been reported in ClinVar (Variation ID 37123). We consider c.202G>A in G6PD to be pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000079404	SCV004809841	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000011157	SCV000031384	other	G6PD ASAHI	2013-10-24	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000079404	SCV000238425	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2015-02-20	no assertion criteria provided	research	This heterozygous variant (c.202G>A; p.Val68Met) has been reported under the name of “Asahi variant” when no other variants are present on the same haplotype; the enzymatic activity was reduced to 41% of wild type. This variant have been previously published as part of the same haplotype (A- variant) which results in reduced enzymatic activity to 10-23% of normal activity.
GenomeConnect, ClinGen	RCV000606259	SCV000784705	not provided	G6PD deficiency		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000079404	SCV000891509	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2017-12-30	no assertion criteria provided	curation
Blueprint Genetics	RCV000224469	SCV000928036	uncertain significance	not provided	2018-11-02	flagged submission	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000079404	SCV001132889	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2019-08-25	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224469	SCV001740287	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000079404	SCV001749894	not provided	Anemia, nonspherocytic hemolytic, due to G6PD deficiency		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-30-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000224469	SCV001808830	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224469	SCV001972631	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000079404	SCV003927912	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-04-01	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000079404	SCV004099377	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-10-30	no assertion criteria provided	clinical testing