chr17-42900935-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000151.4(G6PC1):​c.59A>G​(p.Gln20Arg) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

G6PC1
NM_000151.4 missense

Scores

11
7
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 8.91
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a topological_domain Lumenal (size 27) in uniprot entity G6PC1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000151.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
Variant 17-42900935-A-G is Pathogenic according to our data. Variant chr17-42900935-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1030625.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
G6PC1NM_000151.4 linkuse as main transcriptc.59A>G p.Gln20Arg missense_variant 1/5 ENST00000253801.7
G6PC1NM_001270397.2 linkuse as main transcriptc.59A>G p.Gln20Arg missense_variant 1/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
G6PC1ENST00000253801.7 linkuse as main transcriptc.59A>G p.Gln20Arg missense_variant 1/51 NM_000151.4 P1P35575-1
G6PC1ENST00000592383.5 linkuse as main transcriptc.59A>G p.Gln20Arg missense_variant 1/52 P35575-2
G6PC1ENST00000585489.1 linkuse as main transcriptc.59A>G p.Gln20Arg missense_variant 1/45
G6PC1ENST00000588481.1 linkuse as main transcriptn.124A>G non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 25, 2024- -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsNov 04, 2019This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.49
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
.;D;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Uncertain
0.56
D
MutationAssessor
Uncertain
2.6
M;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-3.5
.;D;.
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
.;D;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.91
MutPred
0.91
Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);
MVP
0.98
MPC
0.82
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.80
gMVP
0.99

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.

Other links and lift over

dbSNP: rs2056021410; hg19: chr17-41052952; COSMIC: COSV53832352; COSMIC: COSV53832352; API