rs137852316

chrX-154532676-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001360016.2(G6PD):c.1178G>A(p.Arg393His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R393C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 25)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:3
• Conservation: PhyloP100: 7.36

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 18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154532677-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-154532676-C-T is Pathogenic according to our data. Variant chrX-154532676-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532676-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.1178G>A	p.Arg393His	missense_variant	10/13	ENST00000393562.10
G6PD	NM_000402.4	c.1268G>A	p.Arg423His	missense_variant	10/13
G6PD	NM_001042351.3	c.1178G>A	p.Arg393His	missense_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.1178G>A	p.Arg393His	missense_variant	10/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 1536798, 16934959, 19224086, 25407525). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010370 / PMID: 1999409). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 1536798, 1999409). Different missense changes at the same codon (p.Arg393Cys, p.Arg393Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001066811, VCV001722672 / PMID: 7655862). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, acute anemia, and CNSHA (PS4_M, PP4). In one family, heizygous brothers both have deficiency and acute or chronic anemia (PP1). Decreased activity in red blood cells (1-33%) (PS3). Within dimer interface (PM1). Predicted to be deleterious by SIFT, Polyphen, and MutationTaster (PP3). Not found in gnomAD (PM2). Reported as pathogenic by Invitae and ARUP Laboratories (PP5). Post_P 0.9997 (odds of pathogenicity 28416, Prior_P 0.1). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 07, 2021	Experimental studies have shown that this variant affects G6PD protein function (PMID: 16934959, 19465117, 25407525). For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 1999409, 1536798). ClinVar contains an entry for this variant (Variation ID: 10370). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 393 of the G6PD protein (p.Arg393His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 20, 2019

The G6PD c.1178G>A; p.Arg393His variant (rs137852316), also known as G6PD Nashville and G6PD Anaheim, has been reported in the literature in individuals and families with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Beutler 1991, Filosa 1992). This variant is reported as pathogenic in ClinVar (Variation ID: 10370) and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1177C>G; p.Arg393Gly) have been reported in individuals with G6PD deficiency and is considered pathogenic (Beutler 1995). The arginine at codon 393 is highly conserved and computation algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be deleterious. Further, functional analyses demonstrate protein instability and impairment (Gomez-Manzo 2014, Wang 2006, Wang 2009). Based on the above information, this variant is considered pathogenic. References: Beutler E et al. DNA sequence abnormalities of human glucose-6-phosphate dehydrogenase variants. J Biol Chem. 1991 Mar 5;266(7):4145-50. Beutler E et al. Three new exon 10 glucose-6-phosphate dehydrogenase mutations. Blood Cells Mol Dis. 1995;21(1):64-72. Filosa S et al. Molecular basis of chronic non-spherocytic haemolytic anaemia: a new G6PD variant (393 Arg----His) with abnormal KmG6P and marked in vivo instability. Br J Haematol. 1992 Jan;80(1):111-6. Gomez-Manzo S et al. The Stability of G6PD Is Affected by Mutations with Different Clinical Phenotypes. Int J Mol Sci. 2014 Nov; 15(11): 21179-21201. Wang X et al. Functional properties of two mutants of human glucose 6-phosphate dehydrogenase, R393G and R393H, corresponding to the clinical variants G6PD Wisconsin and Nashville. Biochim Biophys Acta. 2006;1762(8):767-774. Wang X et al. Clinical mutants of human glucose 6-phosphate dehydrogenase: Impairment of NADP+ binding affects both folding and stability. Biochim Biophys Acta. 2009;1792(8):804-809. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 20, 2023

PP3, PP5, PM2, PS3, PS4_moderate -

G6PD ANAHEIM Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD NASHVILLE Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD PORTICI Other:1

other, no assertion criteria provided

literature only

OMIM

Oct 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;.
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.6	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
Sift4G	Pathogenic	0.0010	D;.;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.84
MutPred		0.96		Loss of MoRF binding (P = 0.1207);Loss of MoRF binding (P = 0.1207);Loss of MoRF binding (P = 0.1207);.;
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.95
gMVP		0.94

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: rs137852316; hg19: chrX-153760891;