rs398123546

chrX-154532390-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 13P and 4B. PM1 PM5 PP3 PP5_Very_Strong BS2

The NM_001360016.2(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:
  • Genomes: 𝑓 0.00017 (1 hom., 5 hem., cov: 25)
  • Exomes 𝑓: 0.000057 (3 hom. 11 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 7.55

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_001360016.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154532389-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751
• PP5: Variant X-154532390-G-A is Pathogenic according to our data. Variant chrX-154532390-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 93493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532390-G-A is described in Lovd as [Pathogenic]. Variant chrX-154532390-G-A is described in Lovd as [Likely_benign]. Variant chrX-154532390-G-A is described in Lovd as [Pathogenic].
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.1360C>T	p.Arg454Cys	missense_variant	11/13	ENST00000393562.10
G6PD	NM_000402.4	c.1450C>T	p.Arg484Cys	missense_variant	11/13
G6PD	NM_001042351.3	c.1360C>T	p.Arg454Cys	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.1360C>T	p.Arg454Cys	missense_variant	11/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes AF: 0.000169 AC: 19 AN: 112662 Hom.: 1 Cov.: 25 AF XY: 0.000144 AC XY: 5 AN XY: 34832

Gnomad AFR AF: 0.000354

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000562

Gnomad SAS AF: 0.000720

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000148 AC: 27 AN: 182006 Hom.: 0 AF XY: 0.0000745 AC XY: 5 AN XY: 67082

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000579

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000574 AC: 63 AN: 1097527 Hom.: 3 Cov.: 40 AF XY: 0.0000303 AC XY: 11 AN XY: 363079

Gnomad4 AFR exome AF: 0.000227

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000232

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000143

Gnomad4 OTH exome AF: 0.000673

GnomAD4 genome AF: 0.000169 AC: 19 AN: 112715 Hom.: 1 Cov.: 25 AF XY: 0.000143 AC XY: 5 AN XY: 34895

Gnomad4 AFR AF: 0.000353

Gnomad4 AMR AF: 0.000280

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000564

Gnomad4 SAS AF: 0.000722

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000669 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:7

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	Revvity Omics, Revvity	Aug 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	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	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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) 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 (PDB). (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 on protein thermostability and decreases 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	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 13, 2022	PS3, PS4, PM5, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Pathogenic:7

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	Eurofins Ntd Llc (ga)	Oct 29, 2013	- -
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	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	G6PD: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -
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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 06, 2014	- -
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. -

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

Oct 29, 2023

- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.81
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;.
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.7	H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.88
MVP		1.0
MPC		2.4
ClinPred		0.33	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123546; hg19: chrX-153760605;