rs5030868
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PM1PP5_Very_StrongBP4BS1_Supporting
The ENST00000393562.10(G6PD):c.563C>T(p.Ser188Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00141 in 1,209,752 control chromosomes in the GnomAD database, including 23 homozygotes. There are 859 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S188S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00072 ( 2 hom., 37 hem., cov: 23)
Exomes 𝑓: 0.0015 ( 21 hom. 822 hem. )
Consequence
G6PD
ENST00000393562.10 missense
ENST00000393562.10 missense
Scores
5
7
4
Clinical Significance
Conservation
PhyloP100: 5.54
Genes affected
G6PD (HGNC:4057): (glucose-6-phosphate dehydrogenase) This gene encodes glucose-6-phosphate dehydrogenase. This protein is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions. G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide ranging levels of enzyme activity and associated clinical symptoms. G6PD deficiency may cause neonatal jaundice, acute hemolysis, or severe chronic non-spherocytic hemolytic anemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in ENST00000393562.10
PP5
Variant X-154534419-G-A is Pathogenic according to our data. Variant chrX-154534419-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 100057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154534419-G-A is described in Lovd as [Pathogenic]. Variant chrX-154534419-G-A is described in Lovd as [Pathogenic]. Variant chrX-154534419-G-A is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.012398928). . Strength limited to SUPPORTING due to the PP5.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00148 (1624/1097898) while in subpopulation MID AF= 0.0435 (180/4135). AF 95% confidence interval is 0.0383. There are 21 homozygotes in gnomad4_exome. There are 822 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| G6PD | NM_001360016.2 | c.563C>T | p.Ser188Phe | missense_variant | 6/13 | ENST00000393562.10 | NP_001346945.1 | |
| G6PD | NM_000402.4 | c.653C>T | p.Ser218Phe | missense_variant | 6/13 | NP_000393.4 | ||
| G6PD | NM_001042351.3 | c.563C>T | p.Ser188Phe | missense_variant | 6/13 | NP_001035810.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| G6PD | ENST00000393562.10 | c.563C>T | p.Ser188Phe | missense_variant | 6/13 | 1 | NM_001360016.2 | ENSP00000377192 | P4 |
Frequencies
GnomAD3 genomes 0.000733 AC: 82AN: 111798Hom.: 2 Cov.: 23 AF XY: 0.00109 AC XY: 37AN XY: 34036
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GnomAD3 exomes AF: 0.00255 AC: 468AN: 183257Hom.: 6 AF XY: 0.00375 AC XY: 254AN XY: 67757
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GnomAD4 exome AF: 0.00148 AC: 1624AN: 1097898Hom.: 21 Cov.: 32 AF XY: 0.00226 AC XY: 822AN XY: 363276
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GnomAD4 genome 0.000724 AC: 81AN: 111854Hom.: 2 Cov.: 23 AF XY: 0.00108 AC XY: 37AN XY: 34102
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:51Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:26
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 02, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 06, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Jul 27, 2022 | ACMG Criteria: PS3, PS4, PP3, PP5; Variant was found in hemizygous state. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 28, 2024 | Criteria applied: PS3,PS4,PP3,PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | May 20, 2023 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 02, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Jul 14, 2018 | - - |
| Pathogenic, no assertion criteria provided | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
| Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | May 08, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 05, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jan 17, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Aug 31, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Apr 23, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 02, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | May 24, 2023 | PS3, PS4, PM1, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Intergen, Intergen Genetics and Rare Diseases Diagnosis Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | 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 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
| Pathogenic, criteria provided, single submitter | curation | Dunham Lab, University of Washington | Aug 12, 2022 | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Aug 13, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Feb 14, 2014 | - - |
not provided Pathogenic:13
| Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Nov 29, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | G6PD: PP1:Strong, PS4, PS3:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 08, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 15, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 03, 2023 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2022 | 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) - |
G6PD deficiency Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 05, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 18, 2023 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | FirmaLab, FirmaLab | - | - - |
Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:2
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | May 31, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Malaria, susceptibility to Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Mar 16, 2021 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2016 | - - |
G6PD deficient hemolytic anemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Hemolytic anemia, G6PD deficient (favism) Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Apr 14, 2020 | 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. - |
G6PD-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 30, 2024 | 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. - |
See cases Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Mar 28, 2023 | ACMG categories: PS3,PM1,PP3,PP5,BP1 - |
G6PD SASSARI Other:1
| other, no assertion criteria provided | literature only | OMIM | May 11, 2018 | - - |
G6PD CAGLIARI Other:1
| other, no assertion criteria provided | literature only | OMIM | May 11, 2018 | - - |
G6PD MEDITERRANEAN Other:1
| other, no assertion criteria provided | literature only | OMIM | May 11, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;.;D;.;D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;D;D;D;D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M;M;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
.;.;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
.;.;D;D;D;D;D
Sift4G
Uncertain
D;.;D;T;.;.;.
Polyphen
B;B;B;.;.;.;.
Vest4
MVP
MPC
0.20
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at