chrX-154532667-G-A

Variant names:

• chrX-154532667-G-A
• rs1557229683
• NM_001360016.2:c.1187C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001360016.2(G6PD):​c.1187C>T​(p.Pro396Leu) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P396A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.32
• Publications: 1 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 12 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-154532668-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1163784.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, 0.995
• PP5: Variant X-154532667-G-A is Pathogenic according to our data. Variant chrX-154532667-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 470161.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.1187C>T	p.Pro396Leu	missense_variant	Exon 10 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1277C>T	p.Pro426Leu	missense_variant	Exon 10 of 13		NP_000393.4
G6PD	NM_001042351.3	c.1187C>T	p.Pro396Leu	missense_variant	Exon 10 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1187C>T	p.Pro396Leu	missense_variant	Exon 10 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Aug 12, 2022

Dunham Lab, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Variant found in hemizygote with deficiency and CNSHA (PP4). Decreased activity in red blood cells (1%) (PS3). Predicted to be damaging or deleterious by multiple computational algorithms (PP3). Within dimer interface (PM1). Not found in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -

Dec 13, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with leucine at codon 396 of the G6PD protein (p.Pro396Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in 2 individuals affected with chronic hemolytic anemia with evidence of segregation in one of the families (PMID: 7959695, Invitae). In addition, a different missense substitution at this codon has been reported de novo in an individual affected with G6PD-deficiency (PMID:26275698). One experimental study has shown that heterozygous females had lower levels of mutant mRNA with this variant as compared to the wild-type mRNA in blood cells, which might indicate a preferential survival of cells where the X inactivation is acting on the mutated chromosome (PMID: 8808605). In summary, this variant is a rare missense change that has been reported in affected individuals and suggested to affect blood cell survival. Additional genetic and functional data are needed to further substantiate the pathogenicity this variant. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;.;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.7	H;H;H;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-9.0	.;.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.93
MutPred		0.97		Gain of catalytic residue at P396 (P = 0.072);Gain of catalytic residue at P396 (P = 0.072);Gain of catalytic residue at P396 (P = 0.072);.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.96
gMVP		1.0
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1557229683; hg19: chrX-153760882;