rs104894563

Positions:

chr17-42911235-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000151.4(G6PC1):c.883C>T(p.Arg295Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,614,040 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R295H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

G6PC1
NM_000151.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 4.87

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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-42911236-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1682529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.927

PP5

Variant 17-42911235-C-T is Pathogenic according to our data. Variant chr17-42911235-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42911235-C-T is described in Lovd as [Pathogenic]. Variant chr17-42911235-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC1	NM_000151.4 linkuse as main transcript	c.883C>T	p.Arg295Cys	missense_variant	5/5	ENST00000253801.7
G6PC1	NM_001270397.2 linkuse as main transcript	c.*275C>T		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC1	ENST00000253801.7 linkuse as main transcript	c.883C>T	p.Arg295Cys	missense_variant	5/5	1	NM_000151.4	P1	P35575-1
G6PC1	ENST00000585489.1 linkuse as main transcript	c.*275C>T		3_prime_UTR_variant	4/4	5
G6PC1	ENST00000592383.5 linkuse as main transcript	c.*275C>T		3_prime_UTR_variant	5/5	2			P35575-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251428

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000965

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely 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:7

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2016	Variant summary: The G6PC c.883C>T (p.Arg295Cys) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/121408 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). This variant has been reported in numerous GSD1a patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 22, 1993	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 28, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 295 of the G6PC protein (p.Arg295Cys). This variant is present in population databases (rs104894563, gnomAD 0.007%). This missense change has been observed in individual(s) with glycogen storage disease type la (PMID: 8211187, 10070617, 12373566, 18083610). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.962C>T. ClinVar contains an entry for this variant (Variation ID: 11999). 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. Experimental studies have shown that this missense change affects G6PC function (PMID: 8211187, 11739393). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The G6PC c.883C>T (p.Arg295Cys) variant was reported in a compound heterozygous state with a second variant in two individuals with glycogen storage disease (GSD) type I and in five alleles from individuals with the disorder (Lei et al. 1993; Lei et al 1995; Stroppiano et al. 1999; Kozak et al. 2000; Matern et al. 2002; Di Rocco et al. 2008). The variant was absent from a total of 14 healthy control individuals but is reported at a frequency of 0.00002 in the Total population of the Exome Aggregation Consortium. Functional studies by Lei et al. (1993) showed that phosphohydrolase activity was abolished in COS1 cells expressing the p.Arg295Cys variant, while research by Shieh et al. (2002) suggested that the p.Arg295Cys variant could cause misfolding and protein degradation. Based on the evidence, the p.Arg295Cys variant is classified as likely pathogenic for glycogen storage disease type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 18, 2014	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 22, 2022	PP4, PM2, PM3, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 13, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.39

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.84

MVP

0.95

MPC

0.93

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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