rs137852326

Positions:

• chrX-154534345-C-A
• chrX-154534345-C-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_001360016.2(G6PD):​c.637G>T​(p.Val213Leu) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:3
• Conservation: PhyloP100: 3.93

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 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant X-154534345-C-A is Pathogenic according to our data. Variant chrX-154534345-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154534345-C-A is described in Lovd as [Pathogenic]. Variant chrX-154534345-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.637G>T	p.Val213Leu	missense_variant	6/13	ENST00000393562.10
G6PD	NM_000402.4	c.727G>T	p.Val243Leu	missense_variant	6/13
G6PD	NM_001042351.3	c.637G>T	p.Val213Leu	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.637G>T	p.Val213Leu	missense_variant	6/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1990	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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. ClinVar contains an entry for this variant (Variation ID: 10383). This variant is also known as G6PD Gastonia. This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 1805484, 1999409; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 213 of the G6PD protein (p.Val213Leu). -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Aug 28, 2014	- -
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). Decreased activity in red blood cells (3-9%) (PS3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 08, 2022	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2021	The G6PD c.637G>T; p.Val213Leu variant (rs137852326), also known as G6PD Marion, G6PD Gastonia and G6PD Minnesota, is reported in the literature in individuals with G6PD deficiency and nonspherocytic hemolytic anemia (Buetler 1991). In addition, this variant has also been reported in an infant with severe hyperbilirubinemia and cholestasis in conjunction with G6PD Cincinnati (Mizukawa 2011). Functional analyses of the variant protein show a significant reduction in enzymatic activity (Buetler 1991). This variant is also reported in ClinVar (Variation ID: 10383). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 213 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.688). Considering available information, this variant is classified as a class I pathogenic variant. 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. Mizukawa B et al. Cooperating G6PD mutations associated with severe neonatal hyperbilirubinemia and cholestasis. Pediatr Blood Cancer. 2011 May;56(5):840-2. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 21, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2019	PS4_moderate, PM1, PM2, PP5, BP4 -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 08, 2021

ACMG categories: PS3,PM2,PP2,PP3,BP1 -

G6PD MINNESOTA Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD MARION Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD GASTONIA 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	0.75
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D;D;.;D;.;D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.8	.;.;N;N;N;N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.024	.;.;D;T;D;D;D
Sift4G	Benign	0.072	T;.;T;D;.;.;.
Polyphen		0.0060	B;B;B;.;.;.;.
Vest4		0.71
MutPred		0.87		Loss of MoRF binding (P = 0.1222);Loss of MoRF binding (P = 0.1222);Loss of MoRF binding (P = 0.1222);Loss of MoRF binding (P = 0.1222);.;.;Loss of MoRF binding (P = 0.1222);
MVP		1.0
MPC		1.2
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.85
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: rs137852326; hg19: chrX-153762560;