ClinVar Miner

Submissions for variant NM_000402.4(G6PD):c.466A>G (p.Asn156Asp) (rs1050829)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000079405 SCV000280712 pathogenic not provided 2015-08-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000307631 SCV000482076 likely benign Glucose 6 phosphate dehydrogenase deficiency 2016-06-14 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000178823 SCV000494243 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2016-06-28 criteria provided, single submitter clinical testing The c.376A>G (p.Asn126Asp) 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). 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). 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 (31.700%). In summary, this variant c.3766A>G (p.Asn126Asp) meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing.
GeneDx RCV000079405 SCV000577148 uncertain significance not provided 2019-01-10 criteria provided, single submitter clinical testing In the African population V68M is commonly present in cis with N126D, and this “A-“ haplotype accounts for 20 to 40% of the population affected with G6PD deficiency in western and central Africa (MIM 305900). The A- haplotype 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).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999876 SCV000603767 likely benign not specified 2018-07-02 criteria provided, single submitter clinical testing
Invitae RCV000178823 SCV000647801 uncertain significance Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2020-01-03 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 126 of the G6PD protein (p.Asn126Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is the A+ (also known as A or A*) haplotype and it is present in population databases (rs1050829, ExAC 32%), being by far the most prevalent in the African subpopulation (PMID: 1303173). ClinVar contains an entry for this variant (Variation ID: 100055). In addition, the c.202G>A (p.Val68Met) variant and the c.376A>G (p.Asn126Asp) variant, when co-occurring in cis c.[202G>A;376A>G], is known as the G6PD A- haplotype which is present in the African populations at 0.2% (PMID: 2572288, 4359638). This variant alone has been reported to be non-deficient and not causative of disease (PMID: 26633385, 9858856, 8611726, 2321910, 1303173, 12737938). However, it has been reported in two individuals affected with drug-induced acute hemolytic anemia who were negative for the p.Val68Met variant, but these individuals could have another G6PD variant that is responsible for the observed phenotype (PMID: 27287612). ClinVar contains an entry for the G6PD A- haplotype (Variation ID: 10361). While this variant alone has been shown to have only a mild affect on 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 allele has been classified as Uncertain Significance.
Blueprint Genetics RCV000079405 SCV000928035 uncertain significance not provided 2018-11-02 criteria provided, single submitter clinical testing
Mendelics RCV000178823 SCV001142113 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 RCV001095678 SCV001251451 pathogenic Glucose 6 phosphate dehydrogenase 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.
Broad Institute Rare Disease Group, Broad Institute RCV000178823 SCV001435245 benign Anemia, nonspherocytic hemolytic, due to G6PD deficiency criteria provided, single submitter research The p.Asn126Asp variant, sometimes called p.Asn156Asp due to a difference in cDNA numbering, in G6PD has been reported as a polymorphism in African individuals in the literature with an allele frequency of 25% in some populations (PMID: 3393536). In vitro functional studies provide some evidence that the p.Asn126Asp variant will not impact protein function (PMID: 3393536). However, these types of assays may not accurately represent biological function. This variant has also been reported in >30% of African chromosomes, 613 hemizygotes, and 354 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for glucose-6-phosphate dehydrogenase deficiency.
Ambry Genetics RCV001267359 SCV001445540 pathogenic Inborn genetic diseases 2018-05-10 criteria provided, single submitter clinical testing
Baylor Genetics RCV000178823 SCV001482574 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-07-27 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000999876 SCV001572469 likely benign not specified 2021-04-08 criteria provided, single submitter clinical testing Variant summary: G6PD c.466A>G (p.Asn156Asp) results in a conservative amino acid change located in the NAD-binding domain (IPR022674) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.026 in 183378 control chromosomes, predominantly at a frequency of 0.32 within the African or African-American subpopulation in the gnomAD database, including 532 homozygous females and 952 hemizygous males. These findings strongly suggest that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.466A>G has been reported in the literature in multiple individuals affected with G6PD Deficiency, however in most of these cases as part of a complex allele with another pathogenic variant, such as c.1058T>C (known as G6PD-Betica or G6PD-Betica Selma), c.292G>A (known as G6PD A-), or c.632A>T (known as G6PD-Santamaria) (e.g. Vulliamy_1988, Beutler_1989, Vulliamy_1996, Djigo_2019). These reports do not provide unequivocal conclusions about association of the variant with disease, as the variant was not identified in isolation in affected individuals. Several publications report experimental evidence evaluating an impact on protein function. The variant, c.466A>G, has been reported to have reduced affinity for substrate molecules compared to wild-type (e.g. Ramirez-Nava_2017), but retains approximately 70-85% of wild-type enzyme activity levels (e.g. Vulliamy_1988). 15 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; uncertain significance, n=3; pathogenic, n=8; other, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
OMIM RCV000011073 SCV000031300 other G6PD A+ 2018-05-11 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000178823 SCV000238427 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2015-02-20 no assertion criteria provided research The heterozygous variant (c.376A>G; p.Asn126Asp) has been previously published by itself under the name of “A variant”; the resulting enzymatic activity of this variant was at 84% 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.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477820 SCV000536703 pathogenic Susceptibility to malaria; Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2015-12-29 no assertion criteria provided research
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000761430 SCV000891508 benign Bone mineral density quantitative trait locus 18 2017-12-30 no assertion criteria provided curation
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000178823 SCV001132890 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-08-25 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000079405 SCV001549316 uncertain significance not provided no assertion criteria provided clinical testing The G6PD p.N126D variant was identified in literature and is commonly known as the A+ allele. When the p.N126D variant is found on the same allele as the G6PD p.V68M variant it is known as the A- allele, and is one of the most common causes G6PD deficiency in the African population (Beutler_1989_PMID:2572288; Clark_2009_PMID:19223928). The variant was identified in dbSNP (ID: rs1050829) and ClinVar (classified as pathogenic by the Center for Pediatric Genomic Medicine, Mendelics, Knight Diagnostic Laboratories, Children's Hospital of Philadelphia and King Abdulaziz Medical City, classified as uncertain significance by GeneDx, BluePrint Genetics and Invitae, classified as likely benign by ARUP Laboratories and Illumina and classified as benign by the Derpatment of Genetics, Qaboos University Hospital Oman). The variant was identified in control databases in 6586 of 205081 chromosomes (722 homozygous; 1760 hemizygous) at a frequency of 0.03211 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 6025 of 18923 chromosomes (freq: 0.3184), Latino in 417 of 28037 chromosomes (freq: 0.01487), Other in 68 of 5335 chromosomes (freq: 0.01275), South Asian in 14 of 19079 chromosomes (freq: 0.000734), European (non-Finnish) in 61 of 92560 chromosomes (freq: 0.000659) and Ashkenazi Jewish in 1 of 7669 chromosomes (freq: 0.00013), but was not observed in the East Asian or European (Finnish) populations. The p.Asn156 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies of the A+ allele (p.N126D variant alone), the p.V68M variant alone, and the A- allele (p.N126D + p.V68M) have demonstrated that the variants alone only cause a slight decrease in activity and enzyme yield, but show significantly decreased activity and enzyme yield when found on the same allele (A-), demonstrating a synergistic effect; therefore the A+ allele on its own is not enough to cause G6PD deficiency (Town_1992_PMID:1303173; Vulliamy_1988_PMID:3393536). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
GenomeConnect - Invitae Patient Insights Network RCV000178823 SCV001749895 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.

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