rs137852334

chrX-154532695-G-A

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.1159C>T(p.Arg387Cys) variant causes a missense change. 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. R387H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 4.59

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, 2 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-154532694-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant X-154532695-G-A is Pathogenic according to our data. Variant chrX-154532695-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532695-G-A is described in Lovd as [Pathogenic]. Variant chrX-154532695-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.1159C>T	p.Arg387Cys	missense_variant	10/13	ENST00000393562.10
G6PD	NM_000402.4	c.1249C>T	p.Arg417Cys	missense_variant	10/13
G6PD	NM_001042351.3	c.1159C>T	p.Arg387Cys	missense_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.1159C>T	p.Arg387Cys	missense_variant	10/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1982	- -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency and CNSHA (PS4_M, PP4). In one family, hemizygote inherited from heterozygous mother (PP1); in another, variant is found in heterozygote but not in either parent so assumed de novo (PM6). Decreased activity in red blood cells (1-14%) and no detectable activity when expressed in E. coli (PS3). Affects same amino acid as pathogenic 387R>C (ClinVar ID 10396) (PM5). Within dimer interface (PM1). Predicted to be damaging or deleterious by multiple computational algorithms (PP3). Not found in gnomAD (PM2). Post_P 0.99996 (odds of pathogenicity 256136, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R387C in G6PD (NM_001042351.3) has been previously reported in individuals affected with Chronic nonspherocytic hemolytic anemia (Keller et al, 2015). Experimental study depicts that the c.1159C >T mutation in the G6PD gene, results in a large reduction of G6PD enzyme activity ie; 14% (Vaca et al, 1982). The p.R387C variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R387C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 387 of G6PD is conserved in all mammalian species. The nucleotide c.1159 in G6PD is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 09, 2022	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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg387 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2602358, 12187030, 29248304; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 10396). This missense change has been observed in individuals with G6PD deficiency (PMID: 1611091). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 387 of the G6PD protein (p.Arg387Cys). -

G6PD GUADALAJARA 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	0.71
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;.
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.0	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
Sift4G	Uncertain	0.022	D;.;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.90
MutPred		0.83		Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);.;
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.97
gMVP		0.98

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: rs137852334; hg19: chrX-153760910;