chrX-154534419-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS1_Supporting
The NM_001360016.2(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 (★★).
Frequency
Consequence
NM_001360016.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| G6PD | NM_001360016.2 | c.563C>T | p.Ser188Phe | missense_variant | Exon 6 of 13 | ENST00000393562.10 | NP_001346945.1 | |
| G6PD | NM_000402.4 | c.653C>T | p.Ser218Phe | missense_variant | Exon 6 of 13 | NP_000393.4 | ||
| G6PD | NM_001042351.3 | c.563C>T | p.Ser188Phe | missense_variant | Exon 6 of 13 | NP_001035810.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000733 AC: 82AN: 111798Hom.: 2 Cov.: 23 AF XY: 0.00109 AC XY: 37AN XY: 34036
GnomAD3 exomes AF: 0.00255 AC: 468AN: 183257Hom.: 6 AF XY: 0.00375 AC XY: 254AN XY: 67757
GnomAD4 exome AF: 0.00148 AC: 1624AN: 1097898Hom.: 21 Cov.: 32 AF XY: 0.00226 AC XY: 822AN XY: 363276
GnomAD4 genome 0.000724 AC: 81AN: 111854Hom.: 2 Cov.: 23 AF XY: 0.00108 AC XY: 37AN XY: 34102
ClinVar
Submissions by phenotype
Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:26
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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 -
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Criteria applied: PS3,PS4,PP3,PP4 -
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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). -
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ACMG Criteria: PS3, PS4, PP3, PP5; Variant was found in hemizygous state. -
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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. -
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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. -
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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). -
PS3, PS4, PM1, PP5 -
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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. -
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not provided Pathogenic:13
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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. -
G6PD: PP1:Strong, PS4, PS3:Moderate -
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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) -
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G6PD deficiency Pathogenic:3
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. -
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. -
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Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:2
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Malaria, susceptibility to Pathogenic:2
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Inborn genetic diseases Pathogenic:1
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G6PD deficient hemolytic anemia Pathogenic:1
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Hemolytic anemia, G6PD deficient (favism) Pathogenic:1
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
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
ACMG categories: PS3,PM1,PP3,PP5,BP1 -
G6PD SASSARI Other:1
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G6PD CAGLIARI Other:1
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G6PD MEDITERRANEAN Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at