chrX-154532990-C-T

Variant names:

• chrX-154532990-C-T
• rs5030869
• NM_001360016.2:c.1003G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_001360016.2(G6PD):​c.1003G>A​(p.Ala335Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,210,823 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.00013 (0 hom. 78 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:23 U:1 O:1
• Conservation: PhyloP100: 0.969

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 7 ACMG points.

• PP5: Variant X-154532990-C-T is Pathogenic according to our data. Variant chrX-154532990-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532990-C-T is described in Lovd as [Pathogenic]. Variant chrX-154532990-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-154532990-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2626309). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.1003G>A	p.Ala335Thr	missense_variant	Exon 9 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1093G>A	p.Ala365Thr	missense_variant	Exon 9 of 13		NP_000393.4
G6PD	NM_001042351.3	c.1003G>A	p.Ala335Thr	missense_variant	Exon 9 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1003G>A	p.Ala335Thr	missense_variant	Exon 9 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes AF: 0.0000798 AC: 9 AN: 112723 Hom.: 0 Cov.: 24 AF XY: 0.0000860 AC XY: 3 AN XY: 34873

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: 0.00183

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000192 AC: 35 AN: 182482 Hom.: 0 AF XY: 0.000341 AC XY: 23 AN XY: 67366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000739

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000135 AC: 148 AN: 1098045 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 78 AN XY: 363445

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: 0.00170

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000356

Gnomad4 OTH exome AF: 0.000369

GnomAD4 genome AF: 0.0000798 AC: 9 AN: 112778 Hom.: 0 Cov.: 24 AF XY: 0.0000859 AC XY: 3 AN XY: 34938

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00183

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000752

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000917 Hom.: 1

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:23 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:13 Uncertain:1

Aug 12, 2022

Dunham Lab, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Variant found in unrelated hemizygotes with deficiency, some with anemia, jaundice, favism, and CNSHA (PS4_M, PP4). In one family, three brothers all have variant and CNSHA (PP1). Decreased activity in red blood cells (0-32%) (PS3). Predicted to be disease causing by Mutation Taster, probably damaging by PolyPhen, and damaging by SIFT (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). -

May 23, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1003G>A(p.Ala335Thr) variant in G6PD gene has been reported previously in homozygous or hemizygous states in multiple individuals affected with G6PD deficiency (Gandomani MG, et. al., 2011; Al-Allawi N, et. al., 2010; Kawamoto F, et. al., 2006). Experimental studies indicate that this variant causes decreased affinity for glucose-6-phosphate and a significant reduction of thermostability, affecting G6PD function (Gandomani MG, et. al., 2011). The p.Ala335Thr variant has been reported with allele frequency of 0.02% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic (multiple submissions). The amino acid change p.Ala335Thr in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 335 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Jul 04, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 335 of the G6PD protein (p.Ala335Thr). This variant is present in population databases (rs5030869, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with glucose-6-phosphatedehydrogenase deficiency (PMID: 3393536, 11499668, 12497642, 15315792, 16927025, 20602793, 21677401, 22293322, 25548459, 26060661). This variant is also known as the Chatham variant. ClinVar contains an entry for this variant (Variation ID: 10363). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 3393536). This variant disrupts the p.Ala335 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7803800, 15625830, 25775246). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 13, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. However, this variant is the second most common variant of G6PD deficiency in several Middle-East countries and in some provinces of Iran (ClinVar ID: VCV000010363). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010363 /PMID: 3393536). Different missense changes at the same codon (p.Ala335Asp, p.Ala335Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001068217 /PMID: 25775246, 7803800). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 haemolytic anaemia (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 alanine to threonine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (12 heterozygotes, 0 homozygotes, 23 hemizygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygotes, 0 hemizygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glucose-6-phosphate dehydrogenase, C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and described as the Chatham variant (ClinVar, PMID: 33100726). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) -

-

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant in exon 9 of the G6PD gene results in the amino acid substitution from Alanine to Threonine at codon 365 (p.Ala365Thr) with the sequence change of c.1093G>A (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (3.8 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The reference base is conserved in mammals 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.1093G>A; p.Ala365Thr variant, also referred to as c.1003G>A; p.Ala335Thr, commonly known as Chatham variant, causes class II of G6PD deficiency characterized by possessing less than 10% of normal enzyme activity, which makes it one of the most severe forms of G6PD deficiency (Gandomani et al. 2011; PMID:21677401). This variant has been reported in multiple individuals affected with glucose-6-phosphatedehydrogenase deficiency and is the second most common variant in several Middle-East countries and in some provinces of Iran (Kashmoola et al., 2015; PMID:25548459, Rahimi Z et al., 2006; PMID:16938474, Iwai et al., PMID:11499668). Experimental studies have shown that this missense change affects substrate affinity and stability of the glucose-6-phosphate dehydrogenase protein (Vulliamy et al., 1988; PMID:3393536) -

Jun 12, 2024

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Jun 13, 2015

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:6

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21931771, 27391121, 28376293, 28824188, 21173806, 14505231, 16927025, 3393536, 28069791, 27980749, 28132692, 34272389, 33069889, 34426522, 12215013, 36007526, 28902532, 38225994, 36150187, 37260775, 38085718, 38480019, 37415281, 37119244, 12028056, 36681081, 36746659) -

Dec 27, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

G6PD: PM2, PM5, PS3:Moderate, PS4:Moderate, PP1, PP4 -

May 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G6PD c.1003G>A; p.Ala335Thr variant (rs5030869), commonly known as G6PD Chatham, is one of the most common G6PD deficiency alleles worldwide and is considered a Class II variant with severe enzymatic deficiency (Gandomani 2011, Mesbah-Namin 2002, Vulliamy 1988). This variant is reported in ClinVar (Variation ID: 10363) and is found predominantly in the South Asian population with an overall allele frequency of 0.13% (25/19065 alleles, including 19 hemizygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.609). Based on available information, this variant is considered to be pathogenic. References: Gandomani MG et al. Molecular identification of G6PD Chatham (G1003A) in Khuzestan province of Iran. J Genet. 2011 Apr;90(1):143-5. PMID: 21677401. Mesbah-Namin SA et al. Three major glucose-6-phosphate dehydrogenase-deficient polymorphic variants identified in Mazandaran state of Iran. Br J Haematol. 2002 Jun;117(3):763-4. PMID: 12028056. Vulliamy TJ et al. Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5171-5. PMID: 3393536. -

Inborn genetic diseases Pathogenic:1

Sep 07, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malaria, susceptibility to Pathogenic:1

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

G6PD-related disorder Pathogenic:1

Apr 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The G6PD c.1003G>A variant is predicted to result in the amino acid substitution p.Ala335Thr. This variant, also known as G6PD Chatham, has previously been reported to be causative for glucose 6 phosphate dehydrogenase deficiency (Vulliamy et al. 1988. PubMed ID: 3393536; Al-Allawi et al. 2010. PubMed ID: 20602793; Iwai et al. 2001. PubMed ID: 11499668). This variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/10363/). This variant is interpreted as pathogenic. -

G6PD CHATHAM Other:1

May 24, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D;D;.;D
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.88	.;.;D;D;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L;L;L;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.84	.;.;N;N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	.;.;D;D;D
Sift4G	Uncertain	0.0090	D;.;D;D;.
Polyphen		0.96	D;D;D;.;.
Vest4		0.51
MVP		0.99
MPC		1.8
ClinPred		0.077	T
GERP RS		5.8
Varity_R		0.81
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5030869; hg19: chrX-153761205;