rs137852320

Positions:

• chrX-154532698-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001360016.2(G6PD):​c.1156A>G​(p.Lys386Glu) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 25)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:4
• Conservation: PhyloP100: 2.29

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792
• PP5: Variant X-154532698-T-C is Pathogenic according to our data. Variant chrX-154532698-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10375.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=3}. Variant chrX-154532698-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.1156A>G	p.Lys386Glu	missense_variant	10/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1246A>G	p.Lys416Glu	missense_variant	10/13		NP_000393.4
G6PD	NM_001042351.3	c.1156A>G	p.Lys386Glu	missense_variant	10/13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1156A>G	p.Lys386Glu	missense_variant	10/13	1	NM_001360016.2	ENSP00000377192	P4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Other:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:2 Uncertain:1

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 and heterozygous maternal grandmother have history of hemolytic anemia (PP1). Decreased activity in red blood cells (1-13%) (PS3). Within dimer interface (PM1). Not found in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.999 (odds of pathogenicity 13661, Prior_P 0.1). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 26, 2021	This sequence change replaces lysine with glutamic acid at codon 386 of the G6PD protein (p.Lys386Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with G6PD deficiency (PMID: 2602358). ClinVar contains an entry for this variant (Variation ID: 10375). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects G6PD function (PMID: 2602358). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 05, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 04, 2016	- -

G6PD-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2024

The G6PD c.1156A>G variant is predicted to result in the amino acid substitution p.Lys386Glu. This variant has been reported to be pathogenic for glucose-6-phosphate dehydrogenase deficiency likely due to altered lysine acetylation (Hirono et al. 1989. PubMed ID: 2602358; Suo et al. 2013. PubMed ID: 23298314). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

G6PD WALTER REED Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD IOWA CITY Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD IOWA Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD SPRINGFIELD 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	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;D;.
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.97	.;.;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Pathogenic	1.4	D
MutationAssessor	Benign	1.3	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	.;.;D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.21	.;.;T;T
Sift4G	Benign	0.57	T;.;T;T
Polyphen		0.61	P;P;P;.
Vest4		0.46
MutPred		0.73		Loss of methylation at K386 (P = 0.004);Loss of methylation at K386 (P = 0.004);Loss of methylation at K386 (P = 0.004);.;
MVP		1.0
MPC		1.4
ClinPred		0.72	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.84
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs137852320; hg19: chrX-153760913;