17-42900989-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000151.4(G6PC1):c.113A>T(p.Asp38Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D38D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

G6PC1
NM_000151.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.42

Variant links:

Genes affected

G6PC1 (HGNC:4056): (glucose-6-phosphatase catalytic subunit 1) Glucose-6-phosphatase (G6Pase) is a multi-subunit integral membrane protein of the endoplasmic reticulum that is composed of a catalytic subunit and transporters for G6P, inorganic phosphate, and glucose. This gene (G6PC) is one of the three glucose-6-phosphatase catalytic-subunit-encoding genes in human: G6PC, G6PC2 and G6PC3. Glucose-6-phosphatase catalyzes the hydrolysis of D-glucose 6-phosphate to D-glucose and orthophosphate and is a key enzyme in glucose homeostasis, functioning in gluconeogenesis and glycogenolysis. Mutations in this gene cause glycogen storage disease type I (GSD1). This disease, also known as von Gierke disease, is a metabolic disorder characterized by severe hypoglycemia associated with the accumulation of glycogen and fat in the liver and kidneys.[provided by RefSeq, Feb 2011]

G6PC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 17-42900989-A-T is Pathogenic according to our data. Variant chr17-42900989-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 12004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC1	NM_000151.4 linkuse as main transcript	c.113A>T	p.Asp38Val	missense_variant	1/5	ENST00000253801.7
G6PC1	NM_001270397.2 linkuse as main transcript	c.113A>T	p.Asp38Val	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC1	ENST00000253801.7 linkuse as main transcript	c.113A>T	p.Asp38Val	missense_variant	1/5	1	NM_000151.4	P1	P35575-1
G6PC1	ENST00000592383.5 linkuse as main transcript	c.113A>T	p.Asp38Val	missense_variant	1/5	2			P35575-2
G6PC1	ENST00000585489.1 linkuse as main transcript	c.113A>T	p.Asp38Val	missense_variant	1/4	5
G6PC1	ENST00000588481.1 linkuse as main transcript	n.178A>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251482

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135914

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 38 of the G6PC protein (p.Asp38Val). This variant is present in population databases (rs104894565, gnomAD 0.002%). This missense change has been observed in individuals with glycogen storage disease type Ia (PMID: 8733042, 9359038, 10070617, 10834516, 11310582). ClinVar contains an entry for this variant (Variation ID: 12004). 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 G6PC protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects G6PC function (PMID: 9359038, 11739393). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2018	Variant summary: G6PC c.113A>T (p.Asp38Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246454 control chromosomes in gnomAD and literature. This frequency is not significantly higher than expected for a pathogenic variant in G6PC causing Glycogen Storage Disease Type Ia (8.1e-06 vs 1.70E-03), allowing no conclusion about variant significance. c.113A>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia, including one confirmed homozygote (Chevalier-Porst_1996, Stroppiano_1999, Reis_2001). 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 abolished enzymatic activity (Chevalier-Porst_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1996	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2022	Published functional studies demonstrate a damaging effect on enzyme activity (Parvari et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11739393, 28074886, 34258141, 8733042, 9359038) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 27, 2023	PP3, PP4, PM2, PM3, PS3, PS4_moderate -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 30, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.50

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.6

M;M;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.56

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.94

MutPred

0.89

Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);

MVP

0.98

MPC

0.96

ClinPred

1.0

GERP RS

5.3

Varity_R

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over