ClinVar Miner

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

gnomAD frequency: 0.03616  dbSNP: rs1050828
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 37
Download table as spreadsheet
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 2022-09-26 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 2023-10-31 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.