ClinVar Miner

Submissions for variant NM_001360016.2(G6PD):c.1360C>T (p.Arg454Cys) (rs398123546)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079396 SCV000225263 pathogenic not provided 2013-10-29 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000079396 SCV000281545 pathogenic not provided 2014-10-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507961 SCV000603769 pathogenic not specified 2019-05-15 criteria provided, single submitter clinical testing The G6PD c.1360C>T; p.Arg454Cys variant (rs398123546), also known as the Union or Maewo variant, has been described in the literature in individuals with severe G6PD deficiency and has been described as a Class II variant associated with a severe decrease in enzyme activity (Ainoon 2003, Calabro 1993, Hsia 1993, Hu 2015, Perng 1992, Silao 1999). It is reported as pathogenic by multiple sources in ClinVar (Variation ID: 93493), and is observed in the general population at an overall frequency of 0.014% (29/203874 alleles, 5 hemizygotes) in the Genome Aggregation Database. The arginine at codon 454 is well conserved across mammals and computational programs (PolyPhen2, SIFT) predict this variant to be deleterious to protein function. Based on available information, this variant is considered pathogenic. REFERENCES Ainoon O et al. Glucose-6-phosphate dehydrogenase (G6PD) variants in Malaysian Malays. Hum Mutat. 2003 Jan;21(1):101. Calabro V et al. Genetic Heterogeneity of Glucose-6-Phosphate Dehydrogenase Deficiency Revealed by Single-Strand Conformation and Sequence Analysis. Am J Hum Genet. 1993;52:527-536. Hsia YE et al. Frequency of glucose-6-phosphate dehydrogenase (G6PD) mutations in Chinese, Filipinos, and Laotians from Hawaii. Hum Genet. 1993;92(5):470-6. Hu R et al. Molecular epidemiological investigation of G6PD deficiency by a gene chip among Chinese Hakka of southern Jiangxi province. Int J Clin Exp Pathol. 2015 Nov 1;8(11):15013-8. Perng LI et al. A novel C to T substitution at nucleotide 1360 of cDNA which abolishes a natural Hha I site accounts for a new G6PD deficiency gene in Chinese. Hum Mol Genet. 1992;1(3): 205. Silao C et al. Molecular basis of glucose-6-phosphate dehydrogenase deficiency among Filipinos. Pediatr Int. 1999 Apr;41(2):138-41.
Invitae RCV000174032 SCV000647799 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 454 of the G6PD protein (p.Arg454Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs398123546, ExAC 0.04%). This variant is a common G6PD mutation which has been reported in multiple individuals affected with G6PD deficiency in different ethnic groups (PMID: 12497642, 26823837, 22293322, 10221015). This variant is also know as the Union variant or the Maewo variant in the literature. ClinVar contains an entry for this variant (Variation ID: 93493). Experimental studies have shown that this variant impacts protein thermostability and decreases catalytic efficiency of the enzyme in vitro (PMID: 16088936). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778894 SCV000915297 pathogenic Glucose 6 phosphate dehydrogenase deficiency 2018-09-20 criteria provided, single submitter clinical testing Across a selection of literature, the G6PD c.1360C>T (p.Arg454Cys) variant has been reported in at least two studies and is found in a total of 37 hemizygous male probands (Calabro et al. 1993; Ganczakowski et al., 1995). Control data are unavailable for this variant, which is reported at a frequency of 0.000623 in the East Asian population of the Genome Aggregation Database. Analysis in proband erythrocytes was measured at 5% of normal levels (Calabro et al. 1993). Wang et al. (2005) measured enzyme kinetics and stability of the p.Arg454Cys variant and found decreased catalytic efficiency and decreased stability of the variant enzyme at higher temperatures compared to wild type. Based on the evidence, the p.Arg454Cys variant is classified as pathogenic for G6PD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000174032 SCV000996202 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2018-10-03 criteria provided, single submitter clinical testing This variant is also known in the literature as c.1360C>T (p.Arg454Cys) and is also commonly described as the "Union" or "Maewo" variant. In the gnomAD population database this variant is present in the heterozygous state at a frequency of 0.014% (29/2038745)and the hemizygous state in 5 individuals. This variant has been reported in the hemizygous state in many individuals affected with G6PD deficiency in different ethnic groups (PMID: 12497642, 26823837, 22293322, 10221015) and is classified by multiple clinical laboratories as pathogenic in the ClinVar database (Variation ID: 93493). Functional in vitro studies demonstrate this variant impacts protein thermostability and decreases catalytic efficiency of the enzyme (PMID: 16088936). Based on the overall evidence, the c.1450C>T (p.Arg484Cys) variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079396 SCV001248070 pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000079396 SCV001251668 pathogenic not provided 2020-05-03 criteria provided, single submitter clinical testing

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