ClinVar Miner

Submissions for variant NM_000402.4(G6PD):c.653C>T (p.Ser218Phe) (rs5030868)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079409 SCV000231598 pathogenic not provided 2017-05-15 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000179363 SCV000236525 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2014-02-14 criteria provided, single submitter clinical testing
UCLA Clinical Genomics Center, UCLA RCV000179363 SCV000255508 likely pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2013-08-13 criteria provided, single submitter clinical testing
GeneDx RCV000079409 SCV000321681 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing The S188F variant in the G6PD gene has been reported numerous times in association with glucose-6-phosphate dehydrogenase deficiency and is commonly found in individuals of mediterranean and middle eastern ancestry (for examples, see Vulliamy et al., 1988; Kurdi-Haidar et al., 1990; Kashmoola et al., 2015). The S188F variant is also associated with acute hemolytic anemia (Vulliamy et al., 1988). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies demonstrate decreased enzyme activity in the circulating erythrocytes of individuals with the S188F variant, increased affinity for G6P and decreased in vitro thermostability (Vulliamy et al., 1988). Based on currently available evidence, we interpret S188F as a pathogenic variant.
Invitae RCV000179363 SCV000647802 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 188 of the G6PD protein (p.Ser188Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs5030868, ExAC 1.6%). This variant is the most common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent, being reported in 60-96% of biochemically diagnosed individuals (PMID: 8611726, 15315792, 16119988, 1978554, 22018328, 24586352). ClinVar contains an entry for this variant (Variation ID: 100057). Experimental studies show that this variant causes protein instability and results in reduced G6PD enzymatic activity in red blood cells of the patients (PMID: 22906047, 24460025, 3393536). In summary, this variant is the most common G6PD deficiency variant in many populations and has been shown to affect protein activity. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000179363 SCV000677998 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2015-06-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623137 SCV000741900 likely pathogenic Inborn genetic diseases 2016-12-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000999760 SCV000885494 pathogenic not specified 2018-11-28 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000477810 SCV000893824 pathogenic Susceptibility to malaria; Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000445579 SCV000915299 pathogenic Glucose 6 phosphate dehydrogenase deficiency 2018-10-19 criteria provided, single submitter clinical testing Across a selection of the available literature, the G6PD c.563C>T (p.Ser188Phe) variant, also called G6PD Mediterranean, has been identified in a homozygous state in six probands, in a hemizygous state in 109 probands and in a heterozygous state in 25 probands (Hellani et al. 2009; Moiz et al. 2012; Santana et al. 2013; Molou et al. 2014 and Jamornthanyawat et al. 2014). The p.Ser188Phe variant was reported in seven of 42 controls in a presumed heterozygous state and is reported at a frequency of 0.017450 in the South Asian population of the Genome Aggregation Database. The p.Ser188Phe variant resulted in 0-7% residual enzyme activity in red blood cells compared to wild type and caused decreased thermostability and reduced catalytic activity (Vulliamy et al. 1988). Based on the collective evidence, the p.Ser188Phe variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics RCV000179363 SCV001142109 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-05-28 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000179363 SCV001150112 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2020-01-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079409 SCV001150542 likely pathogenic not provided 2016-05-01 criteria provided, single submitter clinical testing
OMIM RCV000011086 SCV000031313 other G6PD MEDITERRANEAN 2018-05-11 no assertion criteria provided literature only
OMIM RCV000011087 SCV000031314 other G6PD SASSARI 2018-05-11 no assertion criteria provided literature only
OMIM RCV000011088 SCV000031315 other G6PD CAGLIARI 2018-05-11 no assertion criteria provided literature only
FirmaLab RCV000445579 SCV000106042 pathogenic Glucose 6 phosphate dehydrogenase deficiency no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477810 SCV000536869 pathogenic Susceptibility to malaria; Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2016-05-31 no assertion criteria provided research
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000179363 SCV000854728 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2018-07-14 no assertion criteria provided clinical testing
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000761429 SCV000891507 uncertain significance Angioedema induced by ACE inhibitors, susceptibility to 2017-12-30 no assertion criteria provided curation

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