rs137852349

Variant names:

• chrX-154535996-A-G
• rs137852349
• NM_001360016.2:c.208T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 17P and 1B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong BS2_Supporting

The NM_001360016.2(G6PD):​c.208T>C​(p.Tyr70His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,098,064 control chromosomes in the GnomAD database, including 1 homozygotes. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y70C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (1 hom. 3 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 8.73
• Publications: 13 publications found

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]

G6PD Gene-Disease associations (from GenCC):

• anemia, nonspherocytic hemolytic, due to G6PD deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• G6PD deficiency

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• class I glucose-6-phosphate dehydrogenase deficiency

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 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, 6 uncertain in NM_001360016.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154535995-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 185 curated pathogenic missense variants (we use a threshold of 10). The gene has 42 curated benign missense variants. Gene score misZ: 2.0008 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to anemia, nonspherocytic hemolytic, due to G6PD deficiency, class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant X-154535996-A-G is Pathogenic according to our data. Variant chrX-154535996-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.208T>C	p.Tyr70His	missense_variant	Exon 4 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.298T>C	p.Tyr100His	missense_variant	Exon 4 of 13		NP_000393.4
G6PD	NM_001042351.3	c.208T>C	p.Tyr70His	missense_variant	Exon 4 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.208T>C	p.Tyr70His	missense_variant	Exon 4 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000218 AC: 4 AN: 183344 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000546 AC: 6 AN: 1098064 Hom.: 1 Cov.: 31 AF XY: 0.00000825 AC XY: 3 AN XY: 363428

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40505

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841993

Other (OTH) AF: 0.0000434 AC: 2 AN: 46090

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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 and anemia (PS4_M, PP4). Decreased activity in red blood cells (4-33%) (PS3). Predicted to be damaging by SIFT and PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -

-

Lifecell International Pvt. Ltd

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant in exon 4 of the G6PD gene results in the amino acid substitution from Tyrosine to Histidine at codon 100 (p.Tyr100His) with the sequence change of c.298T>C (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at Lifecell diagnostics. There is a moderate physicochemical difference between Tyrosine and Histidine. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This variant lies in the Glucose-6-phosphate dehydrogenase, NAD binding domain of the Glucose-6-phosphate 1-dehydrogenase protein (http://pfam.xfam.org/family/G6PD_N). This is a Class II variant associated with moderate G6PD deficiency (<10% activity), with intermittent hemolysis. This variant is also known as G6PD Namoru in the literature. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by Arunachalam AK et al., 2019 and Chalvam R., et al. 2007; PMID: 17233850, Ganczakowski M et al. 1995; PMID: 7825590. -

Jun 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs137852349, gnomAD 0.02%). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 70 of the G6PD protein (p.Tyr70His). This missense change has been observed in individual(s) with G6PD-related conditions (PMID: 7825590, 17233850, 33069889). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr70 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7577654, 20621077, 21446359; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 10416). -

Aug 04, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Class II variant according to the WHO classification system, associated with episodes of acute hemolytic anemia and enzyme activity at less than 10% of wild-type (PMID: 28297664); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as G6PD Namoru; This variant is associated with the following publications: (PMID: 7825590, 33069889, 36681081, 25885177, 15727905, 32425388, 38085718, 17611006, 18985093, 26139767, 20713184, 17233850, 8807085, 28297664) -

G6PD NAMORU Other:1

Jul 28, 2016

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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;.;D;.;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;.;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;H;H;.;.;.
PhyloP100		8.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.5	.;.;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;.;D;D;.;.;.
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.58
MutPred		0.92		Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);
MVP		1.0
MPC		0.77
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.94
Mutation Taster		=62/38	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852349; hg19: chrX-153764211;