ClinVar Miner

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

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Total submissions: 7
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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
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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