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

gnomAD frequency: 0.00028  dbSNP: rs5030868

Total submissions: 54

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000179363	SCV000647802	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-01-31	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%), and has an allele count higher than expected for a pathogenic variant. 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 with a positive predictive value of 95%. 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	2023-11-03	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	2023-01-18	criteria provided, single submitter	clinical testing	The G6PD c.563C>T (p.Ser188Phe) missense variant, also referred to as G6PD Mediterranean, results in the substitution of serine at amino acid position 188 with phenylalanine. Across a selection of the available literature, the variant 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 (PMID: 19594365; 22906047; 23479361; 24460025; 24586352). The c.563C>T 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 c.563C>T variant resulted in 0-7% residual enzyme activity in red blood cells compared to wild type and caused decreased thermostability and reduced catalytic activity (PMID: 3393536). Based on the collective evidence, the c.563C>T (p.Ser188Phe) variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency.
Mendelics	RCV000179363	SCV001142109	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	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	2024-08-01	criteria provided, single submitter	clinical testing	G6PD: PP1:Strong, PS4, PS3:Moderate
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	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-06-19	criteria provided, single submitter	clinical testing	Criteria applied: PS4_VSTR,PP3,PP4
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	2023-12-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000179363	SCV001810223	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000179363	SCV002023784	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-01-02	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000179363	SCV002073219	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-05-20	criteria provided, single submitter	clinical testing	The missense variant c.563C>T(p.Ser188Phe) in G6PD gene has been observed in individual(s) with G6PD deficiency (Thedsawad A, et. al., 2022;Arunachalam AK, et. al., 2020; AlJaouni et.al., 2011; Jamornthanyawat et. al., 2014). Experimental studies have shown that this missense change affects G6PD function (Molouet. al., 2014). It is commonly reported in individuals of Mediterranean, Middle Eastern, or Indian ancestry (AlJaouni et. al., 2011;Jamornthanyawat et. al., 2014). The observed variant has been reported with allele frequency of 0.2 % in gnomAD database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). Computational evidence (Polyphen -Benign , SIFT - damaging and MutationTaster -disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Ser188Phe in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 188 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV004584350	SCV002506445	likely pathogenic	See cases	2023-03-28	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM1,PP3,PP5,BP1
3billion	RCV000179363	SCV002572646	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. However, this variant is the most common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent (ClinVar ID: VCV000100057). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22906047 , 24460025 , 3393536). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.49). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000179363	SCV002581618	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-02	criteria provided, single submitter	clinical testing
Dunham Lab, University of Washington	RCV000179363	SCV002599337	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in unrelated hemizygotes with deficiency, many with anemia, jaundice, and favism, and some with CNSHA (PS4_M, PP4). Phenotype transmitted with variant from mother to son (PP1). Decreased activity in red blood cells (0-33%) (PS3). Predicted to be deleterious by REVEL and SIFT (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Not found in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1516, Prior_P 0.1).
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000079409	SCV002818285	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000179363	SCV003921882	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with G6PD deficient haemolytic anaemia (favism) (MIM#300908). (I) 0109 - This gene is associated with X-linked recessive disease. Hemizygous males and homozygous females are commonly affected; however, some heterozygous female carriers can also be affected depending on X-inactivation. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (203 heterozygotes, 6 homozygotes, 256 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glucose-6-phosphate dehydrogenase NAD binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is reported as one of the most common severe pathogenic variants in this gene (ClinVar, LOVD, PMID: 27853304). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The variant has been shown to result in highly impaired enzyme activity (PMID: 3393536, PMID: 7211845). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000179363	SCV003924319	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-05-08	criteria provided, single submitter	research
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000179363	SCV003929453	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency		criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000179363	SCV004013915	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-05-24	criteria provided, single submitter	clinical testing	PS3, PS4, PM1, PP5
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000079409	SCV004024683	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000445579	SCV004122524	pathogenic	G6PD deficiency	2023-10-05	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.653C>T (p.Ser218Phe) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (IPR022675) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 183257 control chromosomes in the gnomAD database, including 6 homozygotes. This variant has a high frequency in South Asian population (0.017) in gnomAD. c.653C>T (Also known as G6PD Mediterranean) is a common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent (Kurdi-Haidar_1990). c.653C>T has been reported in the literature in multiple individuals affected with severe Glucose 6 Phosphate Dehydrogenase Deficiency (Kurdi-Haidar_1990), neonatal hyperbilirubinaemia (Moiz_2012) and hemolytic anemia (examples: Vulliamy_1988, Similuk_2022, and Naofal_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Vulliamy_1988). The following publications have been ascertained in the context of this evaluation (PMID: 36703223, 35753512, 22906047, 3393536, 1978555). Thirty submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
New York Genome Center	RCV000179363	SCV004176061	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-08-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001528124	SCV004195378	pathogenic	Malaria, susceptibility to	2024-03-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000079409	SCV004225543	pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000179363	SCV005038977	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-04-23	criteria provided, single submitter	clinical testing	A heterozygous variant in exon 6 of the G6PD gene that results in the amino acid substitution of Phenylalanine for Serine at codon 188 was detected. The observed variant c.563C>T (p.Ser188Phe) was previously been reported in the 1000 genomes, gnomAD and TOPMed databases with MAF of 0.0833%, 0.1479% and 0.0559% respectively. The in silico prediction of the variant is damaging by SIFT, FATHMM and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000079409	SCV005197994	pathogenic	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV000179363	SCV005382225	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-07-27	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PS4, PP3, PP5; Variant was found in hemizygous state.
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, Sultan Qaboos University	RCV000179363	SCV000891507	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	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
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000179363	SCV004101082	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-11-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925095	SCV004744895	pathogenic	G6PD-related disorder	2024-05-30	no assertion criteria provided	clinical testing	The G6PD c.563C>T variant is predicted to result in the amino acid substitution p.Ser188Phe. This variant, commonly referred to as the "Mediterranean" allele, has been reported to be causative for glucose-6-phosphate dehydrogenase (G6PD) deficiency (see for examples Vulliamy et al. 1988. PubMed ID: 3393536; Yusoff et al. 2002. PubMed ID: 12215013; Moiz et al. 2012. PubMed ID: 22906047). This variant is reported in 1.7% of alleles in individuals of South Asian descent and with a global allele frequency of 0.17% including hundreds of hemizygous individuals and several homozygous individuals. This variant is interpreted as pathogenic.