Total submissions: 39
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000224469 | SCV000111283 | pathogenic | not provided | 2017-03-29 | criteria provided, single submitter | clinical testing | |
Center for Pediatric Genomic Medicine, |
RCV000224469 | SCV000280908 | pathogenic | not provided | 2015-08-24 | criteria provided, single submitter | clinical testing | |
Knight Diagnostic Laboratories, |
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. |
Gene |
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, |
RCV000999820 | SCV000603770 | pathogenic | not specified | 2018-07-02 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
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, |
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, |
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, |
RCV000224469 | SCV001715690 | pathogenic | not provided | 2023-05-19 | criteria provided, single submitter | clinical testing | PS3, PS4 |
Ce |
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, |
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 - |
RCV000079404 | SCV002059871 | pathogenic | Anemia, nonspherocytic hemolytic, due to G6PD deficiency | 2021-11-02 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
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 |
Ai |
RCV000224469 | SCV002503173 | pathogenic | not provided | 2021-07-02 | criteria provided, single submitter | clinical testing | |
Dunham Lab, |
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, |
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, |
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, |
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, |
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, |
RCV000079404 | SCV004809841 | likely pathogenic | Anemia, nonspherocytic hemolytic, due to G6PD deficiency | 2024-04-04 | criteria provided, single submitter | clinical testing | |
Center for Genomic Medicine, |
RCV000224469 | SCV005089783 | pathogenic | not provided | 2024-07-31 | criteria provided, single submitter | clinical testing | |
Institute of Immunology and Genetics Kaiserslautern | RCV000079404 | SCV005382118 | pathogenic | Anemia, nonspherocytic hemolytic, due to G6PD deficiency | 2023-03-10 | criteria provided, single submitter | clinical testing | ACMG Criteria: PS3, PS4, PM2_P, PM5, PP3, PP4, PP5; Variant was found in hemizygous state. |
OMIM | RCV000011157 | SCV000031384 | other | G6PD ASAHI | 2013-10-24 | no assertion criteria provided | literature only | |
Division of Human Genetics, |
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. |
Genome |
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, |
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, |
RCV000079404 | SCV001132889 | pathogenic | Anemia, nonspherocytic hemolytic, due to G6PD deficiency | 2019-08-25 | no assertion criteria provided | clinical testing | |
Diagnostic Laboratory, |
RCV000224469 | SCV001740287 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Genome |
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, |
RCV000224469 | SCV001808830 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000224469 | SCV001972631 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Laboratory Sciences Program |
RCV000079404 | SCV003927912 | pathogenic | Anemia, nonspherocytic hemolytic, due to G6PD deficiency | 2023-04-01 | no assertion criteria provided | clinical testing | |
Zotz- |
RCV000079404 | SCV004099377 | pathogenic | Anemia, nonspherocytic hemolytic, due to G6PD deficiency | 2023-10-30 | no assertion criteria provided | clinical testing |