rs398123546
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong
The ENST00000393562.10(G6PD):c.1360C>T(p.Arg454Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000678 in 1,210,242 control chromosomes in the GnomAD database, including 4 homozygotes. There are 16 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R454H) has been classified as Pathogenic.
Frequency
Consequence
ENST00000393562.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
G6PD | NM_001360016.2 | c.1360C>T | p.Arg454Cys | missense_variant | 11/13 | ENST00000393562.10 | NP_001346945.1 | |
G6PD | NM_000402.4 | c.1450C>T | p.Arg484Cys | missense_variant | 11/13 | NP_000393.4 | ||
G6PD | NM_001042351.3 | c.1360C>T | p.Arg454Cys | missense_variant | 11/13 | NP_001035810.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
G6PD | ENST00000393562.10 | c.1360C>T | p.Arg454Cys | missense_variant | 11/13 | 1 | NM_001360016.2 | ENSP00000377192 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000169 AC: 19AN: 112662Hom.: 1 Cov.: 25 AF XY: 0.000144 AC XY: 5AN XY: 34832
GnomAD3 exomes AF: 0.000148 AC: 27AN: 182006Hom.: 0 AF XY: 0.0000745 AC XY: 5AN XY: 67082
GnomAD4 exome AF: 0.0000574 AC: 63AN: 1097527Hom.: 3 Cov.: 40 AF XY: 0.0000303 AC XY: 11AN XY: 363079
GnomAD4 genome AF: 0.000169 AC: 19AN: 112715Hom.: 1 Cov.: 25 AF XY: 0.000143 AC XY: 5AN XY: 34895
ClinVar
Submissions by phenotype
Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 454 of the G6PD protein (p.Arg454Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with G6PD deficiency (PMID: 10221015, 12497642, 22293322, 26823837). ClinVar contains an entry for this variant (Variation ID: 93493). 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: 16088936). For these reasons, this variant has been classified as Pathogenic. - |
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 hemolytic anemia (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 arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (12 heterozygotes, 1 homozygote, 5 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (0 heterozygotes, 0 homozygotes, 1 hemizygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated G6PD C-terminal domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two alternative nucleotide changes have been reported as pathogenic (ClinVar, PMID: 12105841, 12497642). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most common pathogenic variants, known as the Union or Maewo variant, reported in the literature (ClinVar, PMID: 22293322). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to impact protein thermostability and decrease catalytic efficiency of the enzyme (PMID: 16088936). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | curation | Dunham Lab, University of Washington | Aug 12, 2022 | Variant found in unrelated hemizygotes with deficiency, some with jaundice, anemia, and favism (PS4_M, PP4). In one family, variant segregates with deficiency over multiple generations (PP1). Decreased activity in red blood cells of hemizygotes (0-21%) (PS3). Predicted to be damaging by SIFT, probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.999 (odds of pathogenicity 6563, Prior_P 0.1). - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jul 13, 2022 | PS3, PS4, PM5, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Oct 03, 2018 | This variant is also known in the literature as c.1360C>T (p.Arg454Cys) and is also commonly described as the "Union" or "Maewo" variant. In the gnomAD population database this variant is present in the heterozygous state at a frequency of 0.014% (29/2038745)and the hemizygous state in 5 individuals. This variant has been reported in the hemizygous state in many individuals affected with G6PD deficiency in different ethnic groups (PMID: 12497642, 26823837, 22293322, 10221015) and is classified by multiple clinical laboratories as pathogenic in the ClinVar database (Variation ID: 93493). Functional in vitro studies demonstrate this variant impacts protein thermostability and decreases catalytic efficiency of the enzyme (PMID: 16088936). Based on the overall evidence, the c.1450C>T (p.Arg484Cys) variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 01, 2023 | - - |
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 09, 2023 | The G6PD c.1360C>T; p.Arg454Cys variant (rs398123546), also known as the Union or Maewo variant, has been described in the literature in individuals with severe G6PD deficiency and has been described as a Class II variant associated with a severe decrease in enzyme activity (Ainoon 2003, Calabro 1993, Hsia 1993, Hu 2015, Perng 1992, Silao 1999). It is reported as pathogenic by multiple sources in ClinVar (Variation ID: 93493), and is observed in the general population at an overall frequency of 0.014% (29/203874 alleles, 5 hemizygotes) in the Genome Aggregation Database. The arginine at codon 454 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.938). Based on available information, this variant is considered pathogenic. REFERENCES Ainoon O et al. Glucose-6-phosphate dehydrogenase (G6PD) variants in Malaysian Malays. Hum Mutat. 2003 Jan;21(1):101. Calabro V et al. Genetic Heterogeneity of Glucose-6-Phosphate Dehydrogenase Deficiency Revealed by Single-Strand Conformation and Sequence Analysis. Am J Hum Genet. 1993;52:527-536. Hsia YE et al. Frequency of glucose-6-phosphate dehydrogenase (G6PD) mutations in Chinese, Filipinos, and Laotians from Hawaii. Hum Genet. 1993;92(5):470-6. Hu R et al. Molecular epidemiological investigation of G6PD deficiency by a gene chip among Chinese Hakka of southern Jiangxi province. Int J Clin Exp Pathol. 2015 Nov 1;8(11):15013-8. Perng LI et al. A novel C to T substitution at nucleotide 1360 of cDNA which abolishes a natural Hha I site accounts for a new G6PD deficiency gene in Chinese. Hum Mol Genet. 1992;1(3): 205. Silao C et al. Molecular basis of glucose-6-phosphate dehydrogenase deficiency among Filipinos. Pediatr Int. 1999 Apr;41(2):138-41. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 29, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | G6PD: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2023 | Published functional studies demonstrate a damaging effect by significantly decreasing the kinetic behavior and thermostability of the protein (Wang et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as G6PD Union; This variant is associated with the following publications: (PMID: 1459579, 1303180, 15349799, 22293322, 12497642, 34659341, 8244337, 33637102, 16088936, 8447319, 10221015, 26823837, 28583873, 16136268, 11793482, 31019026, 31980526, 34201899, 34426522, 33072997, 31589614, 36007526, 29251006, 7825590, 33636823, 15727905, 4392654, 31863082) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 06, 2014 | - - |
Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 25, 2022 | - - |
Malaria, susceptibility to Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
G6PD deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 20, 2018 | Across a selection of literature, the G6PD c.1360C>T (p.Arg454Cys) variant has been reported in at least two studies and is found in a total of 37 hemizygous male probands (Calabro et al. 1993; Ganczakowski et al., 1995). Control data are unavailable for this variant, which is reported at a frequency of 0.000623 in the East Asian population of the Genome Aggregation Database. Analysis in proband erythrocytes was measured at 5% of normal levels (Calabro et al. 1993). Wang et al. (2005) measured enzyme kinetics and stability of the p.Arg454Cys variant and found decreased catalytic efficiency and decreased stability of the variant enzyme at higher temperatures compared to wild type. Based on the evidence, the p.Arg454Cys variant is classified as pathogenic for G6PD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at