ClinVar Miner

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

gnomAD frequency: 0.00028  dbSNP: rs5030868
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Total submissions: 36
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) 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 2022-05-05 criteria provided, single submitter clinical testing Published functional studies demonstrate decreased enzyme activity in circulating erythrocytes, increased affinity for G6P, and decreased in vitro thermostability (Vulliamy et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23479361, 27535533, 31152693, 33413378, 31322791, 24460025, 3393536, 27884173, 19594365, 24586352, 1978555, 25548459, 28492530, 8611726, 28492532, 27853304, 27108201, 30097005, 31863082, 33069889, 31019026, 31980526, 34272389, 34426522, 33072997, 33083013, 30755392, 12215013, 32535712, 32860008, 33726816, 1978554, 22906047)
Invitae RCV000179363 SCV000647802 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2021-12-19 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 188 of the G6PD protein (p.Ser188Phe). This variant is present in population databases (rs5030868, gnomAD 1.7%). This missense change has been observed in individual(s) with G6PD deficiency (PMID: 1978554, 8611726, 15315792, 16119988, 22018328, 24586352). It is commonly reported in individuals of Mediterranean, Middle Eastern, or Indian ancestry (PMID: 1978554, 8611726, 15315792, 16119988, 22018328, 24586352). ClinVar contains an entry for this variant (Variation ID: 100057). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function. Experimental studies have shown that this missense change affects G6PD function (PMID: 3393536, 22906047, 24460025). 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 RCV000079409 SCV000885494 pathogenic not provided 2021-12-21 criteria provided, single submitter clinical testing The G6PD c.563C>T; p.Ser188Phe variant (rs5030868), also known as G6PD Mediterranean, is reported in the literature in multiple individuals affected with hemolytic anemia, hyperbilirubinemia and G6PD deficiency (Hellani 2009, Jamornthanyawat 2014, Kaplan 1997, Moiz 2012, Molou 2014, Vulliamy 1988). Functional analyses of the variant protein shows decreased enzyme activity, increased affinity for G6P and decreased in vitro thermostability (Moiz 2012, Molou 2014, Vulliamy 1988). This variant is reported in ClinVar (Variation ID: 100057). This variant is found predominantly in the South Asian population with an allele frequency of 1.7% (331/19,078 alleles, including 4 homozygotes and 211 hemizygotes) in the Genome Aggregation Database. The serine at codon 188 is moderately conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.811). Based on available information, this variant is considered to be pathogenic. References: Hellani A et al. G6PD Mediterranean S188F codon mutation is common among Saudi sickle cell patients and increases the risk of stroke. Genet Test Mol Biomarkers. 2009 Aug;13(4):449-52. Jamornthanyawat N et al. A population survey of the glucose-6-phosphate dehydrogenase (G6PD) 563C>T (Mediterranean) mutation in Afghanistan. PLoS One. 2014 Feb 21;9(2):e88605. Kaplan M et al. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12128-32. Moiz B et al. Neonatal hyperbilirubinemia in infants with G6PD c.563C > T Variant. BMC Pediatr. 2012 Aug 20;12:126. Molou E et al. Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency in Greek newborns: the Mediterranean C563T mutation screening. Scand J Clin Lab Invest. 2014 Apr;74(3):259-63. Vulliamy TJ 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 Jul;85(14):5171-5.
Fulgent Genetics,Fulgent Genetics RCV000477810 SCV000893824 pathogenic Malaria, susceptibility to; Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2018-10-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000445579 SCV000915299 pathogenic G6PD 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 Center for Human Genetics Tuebingen RCV000079409 SCV001150542 pathogenic not provided 2022-06-01 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].
Genome-Nilou Lab RCV000179363 SCV001810223 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2021-07-22 criteria provided, single submitter clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd,Neuberg Centre for Genomic Medicine RCV000179363 SCV002073219 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency criteria provided, single submitter clinical testing The missense variant p.S188F in G6PD (NM_001042351.2) causes the same amino acid change as a previously established pathogenic variant. 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 (Jamornthanyawat et al., 2014; Molou et al., 2014). Experimental studies show that this variant causes protein instability and results in reduced G6PD enzymatic activity in red blood cells of the patients (Vulliamy et al., 1988). 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.
Institute of Human Genetics, University Hospital Muenster RCV002227060 SCV002506445 likely pathogenic Decreased glucose-6-phosphate dehydrogenase level in blood 2019-04-01 criteria provided, single submitter clinical testing ACMG categories: PS3,PM1,PP3,PP5,BP1
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 G6PD deficiency no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477810 SCV000536869 pathogenic Malaria, susceptibility to; 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 Susceptibility to angioedema induced by ACE inhibitors 2017-12-30 no assertion criteria provided curation
Clinical Genetics Laboratory,University Hospital Schleswig-Holstein RCV001528124 SCV001739331 pathogenic Malaria, susceptibility to 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
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000079409 SCV001928877 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000079409 SCV001976349 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000179363 SCV002023784 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2021-06-09 no assertion criteria provided clinical testing

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