rs137852327

chrX-154533122-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 11P and 5B. PM1 PP3 PP5_Very_Strong BP4 BS2

The NM_001360016.2(G6PD):c.871G>A(p.Val291Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,210,676 control chromosomes in the GnomAD database, including 6 homozygotes. There are 48 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 0.00014 (1 hom., 4 hem., cov: 25)
  • Exomes 𝑓: 0.00013 (5 hom. 44 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20 O:2
• Conservation: PhyloP100: 7.25

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 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001360016.2
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, M_CAP, MutationAssessor, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant X-154533122-C-T is Pathogenic according to our data. Variant chrX-154533122-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154533122-C-T is described in Lovd as [Pathogenic]. Variant chrX-154533122-C-T is described in Lovd as [Pathogenic]. Variant chrX-154533122-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-154533122-C-T is described in Lovd as [Likely_benign].
• BP4: Computational evidence support a benign effect (MetaRNN=0.21807534).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.871G>A	p.Val291Met	missense_variant	9/13	ENST00000393562.10
G6PD	NM_000402.4	c.961G>A	p.Val321Met	missense_variant	9/13
G6PD	NM_001042351.3	c.871G>A	p.Val291Met	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.871G>A	p.Val291Met	missense_variant	9/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes AF: 0.000142 AC: 16 AN: 112808 Hom.: 1 Cov.: 25 AF XY: 0.000114 AC XY: 4 AN XY: 34948

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000928

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00393

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000661

GnomAD3 exomes AF: 0.000224 AC: 41 AN: 182854 Hom.: 1 AF XY: 0.000237 AC XY: 16 AN XY: 67562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00253

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000126 AC: 138 AN: 1097815 Hom.: 5 Cov.: 32 AF XY: 0.000121 AC XY: 44 AN XY: 363285

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00146

Gnomad4 SAS exome AF: 0.000443

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.000142 AC: 16 AN: 112861 Hom.: 1 Cov.: 25 AF XY: 0.000114 AC XY: 4 AN XY: 35011

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000927

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00394

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000652

Alfa AF: 0.000100 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000272 AC: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, some with anemia, favism, and jaundice (PS4_M, PP4). Decreased activity in red blood cells (0-29%) (PS3). Predicted to be disease causing by Mutation Taster and probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.997 (odds of pathogenicity 3155, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 15, 2017	- -
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 Valine to Methionine at codon 321 (p.Val321Met) with the sequence change of c.961G>A (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 variant was first identified with glucose-6-phosphate dehydrogenase ( G6PD) deficiency in a person of Laotian ancestry (Beutler et al . 1991) and has since been recorded as the most common variant of G6PD in the Thai and Cambodian populations. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. 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. The G6PD c.961G>A; p.Val321Met variant, also referred to as c.871G>A; p.Val291Met, commonly known as G6PD Viangchan, has been described in the literature as a Class II to Class III pathogenic variant and is associated with a moderate to severe decrease in enzyme activity (Hue et al., 2009; PMID: 19589177, Nuchprayoon et al., 2002; PMID: 11793482). This variant is one of the most common variants associated with Glucose-6-phosphate dehydrogenase (G6PD) deficiency in the Asian population (Beutler et al.,1991; PMID: 1805484, Peng et al., 2005; PMID: 25775246, Ko et al., 2006; PMID: 16777444, Ninokata et al., 2006; PMID: 16528451, Li et al., 2008; PMID: 18329300, Nuchprayoon et al., 2008; PMID: 18046504, Nantakomol et al., 2013; PMID: 23965028, Li et al., 2015; PMID: 26226515). Experimental studies have shown that this missense change impairs G6PD enzyme activity in vitro (Gomez-Manzo et al., 2016; PMID: 27213370 and Boonyuen 2016 et al., PMID: 27053284). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2017	The p.Val321Met (NM_000402.3 c.961G>A) (also referred to as c.871G>A, p.Val291Me t on NM_001042351, G6PD Viangchan and G6PD Jammu) variant in G6PD is one of the most common variants associated with Glucose-6-phosphate dehydrogenase (G6PD) de ficiency in the Asian population and has been reported in several males (hemizyg ous) and females (heterozygous, compound heterozygous, and homozygous) with G6PD deficiency (Beutler 1991, Peng 2005, Ko 2006, Ninokata 2006, Li 2008, Nuchpray oon 2008, Natakomol 2013, Li 2015). It should be noted that most individuals rep orted with this variant were identified through screening by enzyme testing of a pparently healthy individuals at the time of the study. This variant has been re ported in ClinVar (Variation ID#10386) as a pathogenic variant. It has been ide ntified in 0.24% (33/13881) of East Asian chromosomes including 14 hemizygotes b y the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; db SNP rs137852327). In vitro functional studies provide evidence that the p.Val321 Met variant may impact protein function (Boonyuen 2016 and Gomez-Manzo 2016). In summary, although additional studies are required to fully establish its clinic al significance, this variant is likely pathogenic for G6PD deficiency in an X-l inked manner based upon its occurrence in individuals with this disorder and da ta from functional studies. -
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 valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (23 heterozygotes, 1 homozygote, 16 hemizygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is reported as a common pathogenic variant in the Asian population, also referred to as G6PD Viangchan or G6PD Jammu (ClinVar, PMID: 11793482, 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	Revvity Omics, Revvity	Jul 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 291 of the G6PD protein (p.Val291Met). This variant is present in population databases (rs137852327, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with G6PD deficiency (PMID: 15906717, 16155737, 18329300). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10386). 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: 3338798, 27213370). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 05, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	G6PD: PS3, PM1, PS4:Moderate, PP1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 23, 2021	The G6PD c.871G>A; p.Val291Met variant (rs137852327), also known as G6PD Viangchan, is reported in the literature as a Class II pathogenic variant and is associated with a severe decrease in G6PD enzyme activity (Beutler 1994, Hue 2009, Louicharoen 2005, Matsuoka 2005, Nuchprayoon 2008, Nuchprayoon 2002, Peng 2015, Yusoff 2003). Functional analyses of the variant protein also show reduced enzymatic activity and decreased thermal stability (Boonyuen 2016, Gomez-Manzo 2016). This variant is reported in ClinVar (Variation ID: 10386). This variant is found predominantly in the East Asian population with an allele frequency of 0.25% (35/13,844 alleles, including one homozygote and 13 hemizygotes) in the Genome Aggregation Database. The valine at codon 291 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.94). Based on available information, this variant is considered to be pathogenic. References: Beutler E. G6PD deficiency. Blood. 1994 84:3613-3636. Boonyuen U et al. Detailed functional analysis of two clinical glucose-6-phosphate dehydrogenase (G6PD) variants, G6PDViangchan and G6PDViangchan+Mahidol: Decreased stability and catalytic efficiency contribute to the clinical phenotype. Mol Genet Metab. 2016 118:84-91. Gomez-Manzo S et al. Functional and Biochemical Characterization of Three Recombinant Human Glucose-6-Phosphate Dehydrogenase Mutants: Zacatecas, Vanua-Lava and Viangchan. Int J Mol Sci. 2016 17. Hue NT et al. Glucose-6-phosphate dehydrogenase (G6PD) mutations and haemoglobinuria syndrome in the Vietnamese population. Malar J. 2009 8:152. Louicharoen C et al. G6PD Viangchan (871G>A) is the most common G6PD-deficient variant in the Cambodian population. J Hum Genet. 2005 50:448-452. Matsuoka H et al. Glucose-6-phosphate dehydrogenase (G6PD) mutations in Cambodia: G6PD Viangchan (871G>A) is the most common variant in the Cambodian population. J Hum Genet. 2005 50:468-472. Nuchprayoon I et al. Glucose-6-phosphate dehydrogenase mutations in Mon and Burmese of southern Myanmar. J Hum Genet. 2008 53:48-54. Nuchprayoon I et al. Glucose-6-phosphate dehydrogenase (G6PD) mutations in Thailand: G6PD Viangchan (871G>A) is the most common deficiency variant in the Thai population. Hum Mutat. 2002 19:185. Peng Q et al. Large cohort screening of G6PD deficiency and the mutational spectrum in the Dongguan District in Southern China. PLoS One. 2015 10:e0120683. Yusoff NM et al. G6PD Viangchan and G6PD Mediterranean are the main variants in G6PD deficiency in the Malay population of Malaysia. Southeast Asian J Trop Med Public Health. 2003 34 Suppl 3:135-137. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2022	Reported to be a common pathogenic variant in Southeast Asian populations (Nuchprayoon et al., 2002); Published functional studies demonstrate that this variant is associated with lower catalytic constant and catalytic efficiency (Gomez-Manzo et al., 2016); This variant is associated with the following publications: (PMID: 30315739, 26226515, 25775246, 29702993, 30609409, 27053284, 11793482, 29783823, 25536053, 30161219, 3338798, 16136268, 29339739, 11499668, 12850494, 25440321, 23313052, 18329300, 16777444, 1805484, 16155737, 31180159, 34272389, 33072997, 27213370, 31589614, 33083013, 12215013, 27535533) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 18, 2021	PM1, PS3, PS4 -

G6PD deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2024	Variant summary: G6PD c.961G>A (p.Val321Met, also known as G6PD Viangchan) results in a conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal (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 0.00022 in 182854 control chromosomes, predominantly at a frequency of 0.0025 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.00022 vs 0.29), allowing no conclusion about variant significance. c.961G>A has been reported in the literature in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency and has been reported to be a common pathogenic variant in Southeast Asian population (example, Nuchprayoon_2002, Poon_1988). 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 40%-50% of catalytic activity of normal G6PD activities in vitro (Boonyuen_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28583873, 11793482, 3338798). ClinVar contains an entry for this variant (Variation ID: 10386). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The G6PD c.871G>A (p.Val291Met) variant, also referred to as c.961G>A (p.Val321Met), is well described in the literature as a common variant across several Asian populations and is often referred to as G6PD Viangchan or G6PD Jammu. The variant was first identified in an individual of Laotian ancestry with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Beutler et al. 1991) and has since been reported as the most common G6PD variant in the Thai and Cambodian populations: Nuchprayoon et al. (2002) identified the p.Val291Met variant in 43 of 76 Thai G6PD deficiency patients, while the variant was reported in a total of 74 of 81 Cambodian G6PD deficiency patients (Matsuoka et al. 2005; Louicharoen et al. 2005). Control data are not reported in these studies for the p.Val291Met variant, which is reported at a frequency of 0.00785 in the East Asian population of the 1000 Genomes Project. Boonyuen et al. (2016) expressed the p.Val291Met variant in E. coli and reported that the KM for glucose-6-phosphate was similar to that of the wild type protein, though the KM for NADP+ was 5-fold higher than wild type and the kcat showed a 10-fold reduction in catalytic efficiency for NADP+ catalysis. Additionally, the variant showed significantly reduced thermostability as compared to wild type. Based on the collective evidence, the p.Val291Met variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

G6PD deficient hemolytic anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

-

- -

Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 20, 2021

- -

Malaria, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 29, 2023

- -

G6PD JAMMU Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD VIANGCHAN 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	0.77
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.80
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;.;D;.
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.5	H;H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
Sift4G	Pathogenic	0.0010	D;.;D;D;.;.
Polyphen		1.0	D;D;D;.;.;.
Vest4		0.91
MutPred		0.95		Loss of methylation at K290 (P = 0.0177);Loss of methylation at K290 (P = 0.0177);Loss of methylation at K290 (P = 0.0177);.;.;.;
MVP		1.0
MPC		2.1
ClinPred		0.37	T
GERP RS		5.7
Varity_R		0.95
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: rs137852327; hg19: chrX-153761337;