ClinVar Miner

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

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Total submissions: 30
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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 2020-10-26 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 pathogenic Inborn genetic diseases 2016-12-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999760 SCV000885494 pathogenic none provided 2020-05-11 criteria provided, single submitter clinical testing The G6PD c.563C>T; p.Ser188Phe variant, also known as G6PD Mediterranean, has been reported in multiple patients diagnosed with hemolytic anemia and/or hyperbilirubinema (Moiz 2012, Vulliamy 1988). Functional characterization of red blood cells with G6PD Mediterranean indicates a significant decrease of enzymatic activity (class II pathogenic variant), and decreased heat stability (Kirkman 1964, Moiz 2012, Morelli 1984, Vulliamy 1988). Kirkman H et al. Functionally abnormal Glucose 6-Phosphate Dehydrogenases. Cold Spring Harb Symp Quant Biol. 1964; 29:391-8. Moiz B et al. Neonatal hyperbilirubinemia in infants with G6PD c.563C > T Variant. BMC Pediatr. 2012; 12:126. Morelli A et al. G6PD Cagliari: a new low activity glucose 6-phosphate dehydrogenase variant characterized by enhanced intracellular lability. Hum Genet. 1984; 66(1):62-5. Vulliamy T et al. Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci U S A. 1988; 85(14):5171-5.
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
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079409 SCV001150542 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV001250219 SCV001424421 pathogenic G6PD deficient hemolytic anemia criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000179363 SCV001426527 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency criteria provided, single submitter clinical testing
LifeCell International Pvt. Ltd RCV000179363 SCV001430927 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency criteria provided, single submitter clinical testing This variant in exon 6 of the G6PD gene results in the amino acid substitution from Serine to Phenylalanine at codon 188 (p.Ser188Phe) with the sequence change of c.653C>T (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. This variant is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This variant has previously been reported for Anemia, Nonspherocytic Hemolytic, Due to G6pd Deficiency by T J Vulliamy et al., 1988. The Missense Variants Z-Score for this variant is 2.60. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. This variant has been reported six individuals in homozygous condition, in 109 individuals in hemizygous condition and 25 individuals in heterozygous conditions. (Hellani et al. 2009; PMID: 19594365), (Moiz et al. 2012; PMID: 22906047), (Santana et al. 2013; PMID: 23479361), (Molou et al. 2014; PMID: 24460025) and (Jamornthanyawat et al. 2014; PMID: 24586352).
Institute of Human Genetics, University of Leipzig Medical Center RCV000179363 SCV001441024 uncertain significance Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-01-01 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001265539 SCV001443686 pathogenic Hemolytic anemia, G6PD deficient (favism) 2020-04-14 criteria provided, single submitter clinical testing This variant is also known as c.563C>T, p.Ser188Phe (using the alternative transcripts NM_001042351.3 and NM_001360016.2).This alteration has been previously reported as hemizygous change in patients with hemolytic anemia associated with Glucose 6-phosphate deficiency (PMID: 28067620, 24586352, 11445808, 12768444). Functional studies demonstrate decreased enzyme activity in the circulating erythrocytes of individuals with this variant, increased affinity for G6P and decreased in vitro thermostability (PMID: 9342374, 3393536). It is present in the gnomAD population database at a frequency of 0.23% with 471/204697 in heterozygous state, 6/204697 in homozygous state and 256/204697 in hemizygous state. In silico analyses support a deleterious effect of the c.653C>T (p.Ser218Phe) variant on protein function. Based on the available evidence, the c.653C>T (p.Ser218Phe) variant is classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000079409 SCV001447745 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV000179363 SCV001523186 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2020-07-27 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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,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
Institute of Human Genetics, Klinikum rechts der Isar RCV000179363 SCV001150112 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2020-01-17 no assertion criteria provided clinical testing
Clinical Genetics Laboratory,University Hospital Schleswig-Holstein RCV001528124 SCV001739331 pathogenic Susceptibility to malaria 2021-03-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000079409 SCV001741952 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000079409 SCV001807662 pathogenic not provided no assertion criteria provided clinical testing

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