ClinVar Miner

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

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Total submissions: 11
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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 RCV000079405 SCV000603767 likely benign not provided 2017-06-14 criteria provided, single submitter clinical testing The G6PD c.376A>G, p.Asn126Asp variant (rs1050829), also known as G6PD A+, has been reported in multiple individuals of African descent (Yoshida 1967, Takizawa 1987). Functional characterization of the G6PD A+ variant indicates mild decrease of enzymatic activity (84 percent of wildtype) (Yoshida 1967, Vulliamy 1988), and thus considered a class IV variant that generally has no clinical consequences. The variant is listed in ClinVar (Variation ID: 100055), and observed in the general population databases at a frequency of 9.5 percent in the 1000 Genomes Project (34 percent in the African population), 11.4 percent in the Exome Variant Server (31 percent in the African American population), and 3.1 percent in the Genome Aggregation Database (32 percent in the African population). The asparagine at residue 126 is moderately conserved, and computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2, SIFT) predict that the variant has no impact on the protein. Based on the above information, the variant is considered likely benign. References: Takizawa T et al. A single nucleotide base transition is the basis of the common human glucose-6-phosphate dehydrogenase variant A (+). Genomics. 1987; 1(3):228-31. Vulliamy T et al. Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci U S A. 1988; 85(14):5171-5. Yoshida A et al. Negro variant of glucose-6-phosphate dehydrogenase deficiency (A-) in man. Science. 1967; 155(3758):97-9.
Invitae RCV000178823 SCV000647801 uncertain significance Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-01-03 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 mildly 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
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

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