rs137852330

chrX-154534390-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PM1 PM5 PP3_Strong PP5_Very_Strong BS2

The NM_001360016.2(G6PD):c.592C>T(p.Arg198Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,209,974 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. R198H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000011 (0 hom. 8 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.64

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001360016.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154534389-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant X-154534390-G-A is Pathogenic according to our data. Variant chrX-154534390-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154534390-G-A is described in Lovd as [Pathogenic]. Variant chrX-154534390-G-A is described in Lovd as [Pathogenic].
• BS2: High Hemizygotes in GnomAdExome at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.592C>T	p.Arg198Cys	missense_variant	6/13	ENST00000393562.10
G6PD	NM_000402.4	c.682C>T	p.Arg228Cys	missense_variant	6/13
G6PD	NM_001042351.3	c.592C>T	p.Arg198Cys	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.592C>T	p.Arg198Cys	missense_variant	6/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111932 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34114

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000327 AC: 6 AN: 183262 Hom.: 0 AF XY: 0.0000443 AC XY: 3 AN XY: 67766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1097989 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 8 AN XY: 363359

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111985 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34177

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000374

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 198 of the G6PD protein (p.Arg198Cys). This variant is present in population databases (rs137852330, gnomAD 0.02%). This missense change has been observed in individual(s) with G6PD-related conditions (PMID: 1551674, 7789945, 11499668, 16155737, 16927025). This variant is also known as G6PD Coimbra. ClinVar contains an entry for this variant (Variation ID: 10391). 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: 8118045). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, some with jaundice (PS4_M, PP4). Decreased activity in red blood cells (0-8%) (PS3). Located in substrate binding site (PM1). Affects same amino acid as pathogenic 198R>H (ClinVar ID 10417) and 198R>P (ClinVar ID 10394)(PM5). Predicted to be deleterious by in silico algorithms (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Not found in gnomAD (PM2). Post_P 0.9998 (odds of pathogenicity 59154, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 07, 2021	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) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes, 3 hemizygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated NAD binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple individuals with G6PD deficiency and is often referred to as the Coimbra (592C>T) variant. It is commonly reported in hemizygous males, however a few affected heterozygous female carriers have also been identified (ClinVar, PMIDs: 1551674, 12497642, 33051526, 33628497). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Hemizygous males have been reported to have undetectable or severely reduced enzyme activity, classified as class II, whereas a small number of heterozygous females have been reported with moderate G6PD deficiency, classified as class III (PMIDs: 12497642, 22293322, 33051526). (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	Lifecell International Pvt. Ltd	-	This variant in exon 6 of the G6PD gene results in the amino acid substitution from Arginine to Cystine at codon 228 (p.Arg228Cys) with the sequence change of c.682C>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. The observed variant has a minor allele frequency of 0.0000327% in gnomAD database. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This is a Class II variant associated with moderate G6PD deficiency (<10% activity), with intermittent hemolysis. The G6PD c.682C>T; p.Arg228Cys variant, also referred to as c.592C>T; p.Arg198Cys, commonly known as G6PD-Coimbra or Shunde or Vancouver in the literature. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by (He Y et al., 2020 PMID: 33051526; Islam MT et al., 2018 PMID: 30097005; Lee J et al., 2018 PMID: 29548282) -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.592C>T(p.Arg198Cys) variant in G6PD gene has been reported previously in individual(s) affected with G6PD-related conditions (Roca-Feltrer A, et. al., 2014; Nuchprayoon I, et. al., 2008). Experimental studies show that this variant affects G6PD function (Jiang W, et. al., 2006). The p.Arg198Cys variant has been reported with allele frequency of 0.003% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid change p.Arg198Cys in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 198 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Malaria, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 18, 2023

- -

G6PD COIMBRA Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.83
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;.;D;.;D
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.6	H;H;H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
Sift4G	Pathogenic	0.0	D;.;D;D;.;.;.
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.87
MutPred		0.98		Loss of disorder (P = 0.1044);Loss of disorder (P = 0.1044);Loss of disorder (P = 0.1044);Loss of disorder (P = 0.1044);.;.;Loss of disorder (P = 0.1044);
MVP		1.0
MPC		0.84
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0

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: rs137852330; hg19: chrX-153762605;