ClinVar Miner

Submissions for variant NM_001360016.2(G6PD):c.968T>C (p.Leu323Pro) (rs76723693)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000757319 SCV000233011 pathogenic not provided 2014-02-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999866 SCV000885492 pathogenic not specified 2018-11-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000011119 SCV000915298 likely pathogenic Glucose 6 phosphate dehydrogenase deficiency 2019-01-11 criteria provided, single submitter clinical testing The G6PD c.968T>C (p.Leu323Pro) variant is a missense variant. Benmansour et al. (2013) reported the variant in a heterozygous state in two individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency as well as in a hemizygous state in one individual with a measured residual enzyme activity of 51% of wildtype. The p.Leu323Pro variant is commonly referred to as G6PD Nefza. This variant is more commonly reported in cis with another variant, p.Asn126Asp, which is referred to as G6PD A-; this complex allele has been identified in 76/1039 (7%) of individuals with G6PD deficiency (Beutler et al. 1989; Hamel et al. 2002; Monteiro et al. 2014; Reading et al. 2017). The p.Leu323Pro variant is reported at a frequency of 0.009970 in the African population of the 1000 Genomes Project. Functional studies in E. coli demonstrated the p.Leu323Pro variant shows 50% residual activity compared to the wildtype enzyme and results in reduced substrate affinity and G6PD expression (Ramirez-Nava et al. 2017). Importantly, comprehensive studies of the p.Leu323Pro, p.Asn126Asp, and complex alleles suggested the p.Leu323Pro variant was the primary contributor to the alterations in catalytic activity and structural modifications observed for the complex allele. Based on the available evidence, the p.Leu323Pro variant is classified as likely pathogenic for glucose-6-phosphate dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000818410 SCV000959021 uncertain significance Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2018-08-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 323 of the G6PD protein (p.Leu323Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs76723693, ExAC 0.6%). The c.968T>C (p.Leu323Pro) variant and the c.376A>G (p.Asn126Asp) variant, when co-occurring in cis, is known as G6PD Betica or G6PD Selma c.[376A>G; 968T>C], which is a subtype of the G6PD A- haplotype (PMID: 18056001, 2572288, 25915902, 27413522). The c.[376A>G; 968T>C] G6PD A- haplotype is the most prevalent G6PD deficiency variant in the Gambian population at 7% (PMID: 24615128, 26738565, 28067620). This variant alone has been reported in an individual affected with neonatal jaundice and hemolytic anemia triggered by fava beans (favism) (PMID: 22963789). ClinVar contains an entry for this variant (Variation ID: 10388). While the c.968T>C (p.Leu323Pro) variant alone has been shown to only mildly affect enzyme activity, the c.[376A>G; 968T>C] changes of the G6PD A- haplotype have been reported to act synergistically to cause dramatic reduction of the enzymatic activity of the G6PD protein (PMID: 18177777, 2633878, 2572288, 28067620, 28195434). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000818410 SCV001142105 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000818410 SCV001572468 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2021-04-08 criteria provided, single submitter clinical testing Variant summary: G6PD c.1058T>C (p.Leu353Pro) results in a non-conservative amino acid change located in the C-terminal domain (IPR022675) of the encoded protein sequence. This variant has also been reported in the literature as c.968T>C (p.Leu323Pro) in transcript NM_001042351, and has been referred to as G6PD-Nefza. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 183074 control chromosomes in the gnomAD database, including 1 homozygote. c.1058T>C has been reported in the literature in multiple individuals affected with G6PD Deficiency. In most of these individuals, the variant was found in cis with a second variant in G6PD, c.466A>G (p.Asn156Asp; also known as c.376A>G, p.Asn126Asp) (e.g. Beutler_1989, Xu_1995, Vulliamy_1996, Rodrigues_2002, DeAraujo_2006, Jalloh_2008, Benkerrou_2013, Dijgo_2019). This complex allele [c.466A>G, c.1058T>C] has been referred to as "G6PD Betica or "G6PD Betica-Selma" in the literature. Experimental evidence has reported a reduction in G6PD activity in cells expressing either [c.466A>G, c.1058T>C] or c.1058T>C in isolation. In the same study, c.1058T>C was also shown to significantly reduce affinity for substrates G6P and NADP+ (Ramirez-Nava_2017). At least one publication reports the c.1058T>C variant in isolation in an individual who was diagnosed with hemolytic anemia after ingestion of fava beans (Benmansour_2013). This patient had a family history of G6PD deficiency, and G6PD activity in his cells was assessed to be approximately 51% that of wild-type. Collectively, these findings indicate that c.1058T>C is very likely to be associated with disease. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as pathogenic/likely pathogenic (n=5) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000757319 SCV001873905 likely pathogenic not provided 2021-04-26 criteria provided, single submitter clinical testing Typically seen in cis with the N126D variant, which has also been reported in cis with other G6PD variants in individuals with G6PD deficiency, and does not lead to symptoms when present without a second variant (Mason et al., 2007); Functional studies demonstrate that L323P is associated with decreased G6PD activity and a lower catalytic constant, which is greater than that seen with N126D by itself, but is even more pronounced when the two variants are found in combination (Ramirez-Nava et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 30755392, 31564435, 28067620, 30071859, 30508000, 30409136, 30204801, 31525211, 30206300, 2836867, 3393536, 2633878, 12367584, 18177777, 22963798, 25141282, 28195434, 29072585, 19782058, 21929367, 25071003, 17611006, 23006493, 2572288, 27267757, 27941691, 11852882, 22009270, 26738565, 21931771, 22963789, 24615128, 22237549)
OMIM RCV000011119 SCV000031346 pathogenic Glucose 6 phosphate dehydrogenase deficiency 1988-06-01 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000011119 SCV001142505 pathogenic Glucose 6 phosphate dehydrogenase deficiency 2020-01-06 no assertion criteria provided curation NM_001042351.1:c.968T>C in the G6PD gene has an allele frequency of 0.005 in African subpopulation in the gnomAD database. This variant is more commonly reported in cis with another variant, p.Asn126Asp, which is referred to as G6PD A-; this complex allele has been identified in 76/1039 (7%) of individuals with G6PD deficiency (PMID: 2572288; 12367584; 25141282; 28195434). Functional studies demonstrated the p.Leu323Pro has a major contribution to the loss of affinity for both substrates in the double mutant G6PD A- (PMID29072585). Pathogenic computational verdict because 9 pathogenic predictions from DANN, DEOGEN2, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PS4; PP4; PP3;

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