rs137852342

Positions:

• chrX-154532969-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1 PP5 BP4 BS2_Supporting

The NM_001360016.2(G6PD):​c.1024C>T​(p.Leu342Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000215 in 1,210,867 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000019 (0 hom. 5 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:3 O:1
• Conservation: PhyloP100: 5.29

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 1 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, 5 uncertain in NM_001360016.2
• PP5: Variant X-154532969-G-A is Pathogenic according to our data. Variant chrX-154532969-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10405.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=2, Uncertain_significance=3}. Variant chrX-154532969-G-A is described in Lovd as [Pathogenic]. Variant chrX-154532969-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.13903645). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAdExome4 at 5 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/exons	MANE	UniProt
G6PD	NM_001360016.2	c.1024C>T	p.Leu342Phe	missense_variant	9/13	ENST00000393562.10
G6PD	NM_000402.4	c.1114C>T	p.Leu372Phe	missense_variant	9/13
G6PD	NM_001042351.3	c.1024C>T	p.Leu342Phe	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.1024C>T	p.Leu342Phe	missense_variant	9/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000444 AC: 5 AN: 112603 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34767

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00140

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000137 AC: 25 AN: 183026 Hom.: 0 AF XY: 0.000104 AC XY: 7 AN XY: 67564

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00166

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000191 AC: 21 AN: 1098212 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 5 AN XY: 363580

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000629

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000444 AC: 5 AN: 112655 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34829

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00141

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, some with anemia (PS4_M, PP4). Also found in two heterozygous sisters with deficiency who inherited this variant (c.1024C>T) from father and c.383T>C from mother (PP1). Decreased activity in red blood cells (2-39%) (PS3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 12, 2021	This sequence change replaces leucine with phenylalanine at codon 342 of the G6PD protein (p.Leu342Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 8364584, 10502785, 16329560, 20203002, 30045279, 30315739). This variant is also known as C13184T or Chinese-5. ClinVar contains an entry for this variant (Variation ID: 10405). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 28, 2017	- -

Niemann-Pick disease, type C Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 15, 2024

Variant summary: NPC1 c.1114C>T (p.Arg372Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251162 control chromosomes. c.1114C>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

G6PD deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 15, 2024

Variant summary: G6PD c.1114C>T (p.Leu372Phe, also known as Chinese-5) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (IPR022675) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 183026 control chromosomes with 7 hemizygotes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.00014 vs 0.29), allowing no conclusion about variant significance. c.1114C>T has been reported in the literature in many individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (example, Wang_2021, Fu_2018). These data indicate that the variant is very likely to be associated with disease. At least 7 studies report experimental evidence evaluating an impact on protein function using hemizygote cells, the average G6PD activity appeared to be 30-40% of normal activity (Geck_2023). The following publications have been ascertained in the context of this evaluation (PMID: 29339739, 36681081, 34659341). ClinVar contains an entry for this variant (Variation ID: 10405). Based on the evidence outlined above, the variant was classified as pathogenic. -

Metachromatic leukodystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 15, 2024

Variant summary: ARSA c.1114C>T (p.Arg372Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250080 control chromosomes. c.1114C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Biffi_2008, Heinisch_1995, Fumagalli_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

G6PD MAHIDOL-LIKE Other:1

other, no assertion criteria provided

literature only

OMIM

Apr 18, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.61
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.84	D;D;D;.
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	0.18	T;.;T;T
Polyphen		0.69	P;P;P;.
Vest4		0.77
MVP		1.0
MPC		1.5
ClinPred		0.12	T
GERP RS		4.0
Varity_R		0.67
gMVP		0.98

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: rs137852342; hg19: chrX-153761184;