ClinVar Miner

Submissions for variant NM_000402.4(G6PD):c.292G>A (p.Val98Met) (rs1050828)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000224469 SCV000603770 pathogenic not provided 2017-07-07 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000224469 SCV000928036 uncertain significance not provided 2018-11-02 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
Counsyl RCV000079404 SCV000677948 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2015-10-15 criteria provided, single submitter clinical testing
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000761431 SCV000891509 uncertain significance Parkinsonism with spasticity, X-linked 2017-12-30 no assertion criteria provided curation
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224469 SCV000111283 pathogenic not provided 2017-03-29 criteria provided, single submitter clinical testing
GeneDx RCV000224469 SCV000577149 pathogenic not provided 2018-12-25 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).
GenomeConnect, ClinGen RCV000606259 SCV000784705 not provided Glucose 6 phosphate dehydrogenase 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.
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.
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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000079404 SCV000711717 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2016-06-27 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 G6PD deficiency and has been shown to alter G6PD enzyme activity (Hirono 2002, Shah 2014). This var iant has also been identified in 11% (955/8415) of African chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs105082 8). The variant's high frequency is consistent with the prevalence of G6PD defic iency in African populations and is thought to be a result of a partial protecti on against malaria (Manjurano 2012). The p.Val98Met variant is most frequently f ound in association with the common p.Asn156Asp allele. This combination indicat es the G6PD A- allele, which is a class III variant with a moderate level of def iciency (10-60% activity). In summary, the p.Val98Met meets criteria to be class ified as pathogenic for G6PD deficiency in an X-linked manner.
OMIM RCV000011157 SCV000031384 other G6PD ASAHI 2013-10-24 no assertion criteria provided literature only
PharmGKB RCV000211231 SCV000268145 drug response chlorproguanil and dapsone response - Toxicity/ADR 2015-10-14 reviewed by expert panel curation PharmGKB Level of Evidence 1B: Annotation for a variant-drug combination where the preponderance of evidence shows an association. The association must be replicated in more than one cohort with significant p-values, and preferably will have a strong effect size.

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