rs137852339

chrX-154533044-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 10P and 5B. PM1 PP5_Very_Strong BP4 BS2

The NM_001360016.2(G6PD):c.949G>A(p.Glu317Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000563 in 1,211,171 control chromosomes in the GnomAD database, including 7 homozygotes. There are 376 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 20 hem., cov: 24)
  • Exomes 𝑓: 0.00059 (7 hom. 356 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:3
• Conservation: PhyloP100: 2.83

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001360016.2
• PP5: Variant X-154533044-C-T is Pathogenic according to our data. Variant chrX-154533044-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154533044-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.013208687).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAd at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.949G>A	p.Glu317Lys	missense_variant	9/13	ENST00000393562.10
G6PD	NM_000402.4	c.1039G>A	p.Glu347Lys	missense_variant	9/13
G6PD	NM_001042351.3	c.949G>A	p.Glu317Lys	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.949G>A	p.Glu317Lys	missense_variant	9/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 29 AN: 113000 Hom.: 0 Cov.: 24 AF XY: 0.000569 AC XY: 20 AN XY: 35142

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: 0.00909

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000751

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00124 AC: 227 AN: 183230 Hom.: 1 AF XY: 0.00195 AC XY: 132 AN XY: 67742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000612

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000595 AC: 653 AN: 1098117 Hom.: 7 Cov.: 33 AF XY: 0.000979 AC XY: 356 AN XY: 363511

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: 0.0111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.000781

GnomAD4 genome AF: 0.000257 AC: 29 AN: 113054 Hom.: 0 Cov.: 24 AF XY: 0.000568 AC XY: 20 AN XY: 35206

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000751

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000167 Hom.: 1

Bravo AF: 0.0000982

ExAC AF: 0.00166 AC: 202

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	This variant in exon 9 of the G6PD gene results in the amino acid substitution from glutamic acid to lysine at codon 347 (p.Glu347Lys) with the sequence change of c.1039G>A (NM_000402.4). This variant was observed in a proband with a decreased level of G6PD enzyme (3.1 U/dl) which was screened for advanced newborn screening with confirmatory genetic reflex testing at Lifecell diagnostics. There is a small physicochemical difference between glutamic acid and lysine. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This is a Class III variant associated with moderate G6PD deficiency (10-60% enzyme activity) and hemolysis with stressors only. According to the previous studies this variant is also known as G6PD Kerala, G6PD Kalyan, G6PD Kerala Kalyan, G6PD Jamnaga, and G6PD Rohini. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by Islam MT et al., 2018. 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 is a prevalent G6PD variant in the South Asian population, typically associated with partial reduction of enzyme activity (Ahluwalia A et al. 1992; PMID: 1303182), (Islam MT et al. 2018; PMID: 30097005), ( Ninokata A et al, 2006; PMID: 16528451), ( Sukumar S et al. 2004; PMID: 15315792), ( Sarker SK et al. 2016; PMID: 27880809), (Minucci A et al, 2012; PMID: 22293322). -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with G6PD deficiency but no other symptoms (PS4_M, PP4). Also segregates with deficiency in multiple brothers, and heterozygous sister has slightly decreased activity (PP1). Decreased activity in red blood cells of hemizygotes (19-52%) (PS3). Modeling predicts disruption of function (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The amino acid Glu at position 347 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. This variant is a prevalent G6PD variant in the South Asian population, typically associated with partial reduction of enzyme activity (Ahluwalia A et al, Islam MT et al). By WHO classification, this is a Class III variant associated with moderate G6PD deficiency (10-60% enzyme activity) and hemolysis with stressors only (Minucci A et al). This variant is also known as G6PD Kerala, G6PD Kalyan, G6PD Kerala–Kalyan, G6PD Jamnagar, and G6PD Rohini in the literature. The p.Glu347Lys variant in reported with the allele frequency of 0.1111% in gnomAD Exomes and is novel (not in any individuals) in1000 Genomes. This variant has been reported in Clinvar as Conflicting interpretations of pathogenicity - pathogenic/ uncertain significance. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu347Lys in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 317 of the G6PD protein (p.Glu317Lys). This variant is present in population databases (rs137852339, gnomAD 1.1%), and has an allele count higher than expected for a pathogenic variant. This variant is a prevalent G6PD variant in the South Asian population, typically associated with partial reduction of enzyme activity (PMID: 1303182, 30097005, 16528451, 15315792, 30097005, 27880809, 27535533). By WHO classification, this is a Class III variant associated with moderate G6PD deficiency (10-60% enzyme activity) and hemolysis with stressors only (PMID: 22293322). This variant is also known as G6PD Kerala, G6PD Kalyan, G6PD Kerala–Kalyan, G6PD Jamnaga, and G6PD Rohini. ClinVar contains an entry for this variant (Variation ID: 10401). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on G6PD protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 03, 2023	The hemizygous, maternally inherited c.949G>A p.(Glu317Lys) variant identified in the G6PD gene substitutes an evolutionarily conserved glutamic acid with Lysine at position 317/516 (exon 9/13) in the dimer interface region [PMID: 31294066] of the encoded protein. This variant is also called c.1039G>Ap.(Glu347Lys) based on transcript NM_000402.4, and is reported in ClinVar [ClinVar ID:10401] as Pathogenic. This variant is observed in 322 alleles (0.04% minor allele frequency with 6 homozygotes and 151 hemizygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us) including in 242 alleles(1.07% minor allele frequency with 1 homozygote and 148 hemizygotes) in South Asian subpopulation (gnomAD v2.1.1 and v3.1.2(non-Topmed)). In silico predictions are in favor of damaging effect for p.(Glu317Lys) (REVEL = 0.648). The p.(Glu317Lys) variant in G6PD has previously been reported in individuals with G6PD deficiency and is also known as G6PD Kerala, G6PD Kalyan, G6PD Kerala Kalyan, G6PD Jamnagar, and G6PD Rohini in the literature [(PMID: 15996881, 1303182, 30097005,16528451, 15315792, 27880809, 27535533, 33069889]. The c.949G>A p.(Glu317Lys) variant in G6PD is reported as Class III variant according to WHO classification and associated with moderate G6PD deficiency (10-60% enzyme activity) and hemolysis with stressors only [PMID:15996881,22293322]. Based on available evidence this maternally inherited hemizygous c.949G>A p.(Glu317Lys) variant identified in the G6PD gene is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

3-Methylglutaconic aciduria type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 22, 2020

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. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - Variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 94 heterozygotes, 1 homozygote, 132 hemizygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated G6PD C-terminal domain (DECIPHER). (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been classified as a G6PD Class III variant and is known as the Kerala-Kalyan variant. Individuals with this variant have moderate to mild G6PD enzyme activity (WHO recommendations; G6PD database; PMID: 22293322; 30097005, 31833391). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Malaria, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 11, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

G6PD: PS3, PS4, PP1, PP2 -

G6PD deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 05, 2021

The G6PD c.1039G>A (p. Glu347Lys) missense variant, which is also commonly reported as c.949G>A (p.Glu317Lys) and G6PD Kerala-Kalyan, and less commonly reported as G6PD Jamnagar or Rohini, is one of the most common disease-causing variants in South Asian populations. The p.Glu347Lys variant has been estimated to account for between 1.1% and 24.5% of disease-causing alleles in the Indian population (Sukumar et al. 2004; Devendra et al. 2020). This variant has also been reported in affected individuals of Bangladeshi, Burmese, and Thai descent (Nuchprayoon et al. 2008; Sarker et al. 2016). The p.Glu347Lys variant is typically associated with glucose-6-phosphate dehydrogenase enzyme activity levels between 10% - 60% of wild type and is considered a class III variant according the WHO classification system for G6PD variants (Minucci et al. 2012; Harcke et al. 2019). The p.Glu347Lys variant is reported at a frequency of 0.01138 in the South Asian population of the Genome Aggregation Database. This allele frequency is high but is consistent with the disease prevalence estimates. Although the consequences of p.Glu347Lys have not been characterized experimentally, the Glu347 residue is known to interact with Lys275, which is the site of the another disease-causing variant, p.Lys275Asn or G6PD Bangkok. This interaction forms a salt bridge between subunits B and C of the tetrameric structure in wild-type G6PD (Boonyuen et al. 2017). Based on the collective evidence and application of the ACMG criteria, the p. Glu347Lys variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. -

G6PD KERALA Other:1

other, no assertion criteria provided

literature only

OMIM

Apr 18, 2013

- -

G6PD KERALA-KALYAN Other:1

other, no assertion criteria provided

literature only

OMIM

Apr 18, 2013

- -

G6PD KALYAN Other:1

other, no assertion criteria provided

literature only

OMIM

Apr 18, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;D;.;D;.
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
Sift4G	Benign	0.32	T;.;T;T;.;.
Polyphen		0.84	P;P;P;.;.;.
Vest4		0.51
MutPred		0.84		Gain of ubiquitination at E317 (P = 0.0048);Gain of ubiquitination at E317 (P = 0.0048);Gain of ubiquitination at E317 (P = 0.0048);.;.;.;
MVP		1.0
MPC		1.2
ClinPred		0.073	T
GERP RS		5.5
Varity_R		0.77
gMVP		0.89

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: rs137852339; hg19: chrX-153761259; COSMIC: COSV104423998; COSMIC: COSV104423998;