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

gnomAD frequency: 0.00028  dbSNP: rs5030868

Total submissions: 36

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