17-42900935-A-G

Variant names:

• chr17-42900935-A-G
• rs2056021410
• NM_000151.4:c.59A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 8.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• 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=2, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC1	NM_000151.4	c.59A>G	p.Gln20Arg	missense_variant	Exon 1 of 5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.59A>G	p.Gln20Arg	missense_variant	Exon 1 of 5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.59A>G	p.Gln20Arg	missense_variant	Exon 1 of 5	1	NM_000151.4	ENSP00000253801.1
G6PC1	ENST00000592383.5	c.59A>G	p.Gln20Arg	missense_variant	Exon 1 of 5	2		ENSP00000465958.1
G6PC1	ENST00000585489.1	c.59A>G	p.Gln20Arg	missense_variant	Exon 1 of 4	5		ENSP00000466202.1
G6PC1	ENST00000588481.1	n.124A>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:2 Uncertain:1

Feb 19, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: G6PC1 c.59A>G (p.Gln20Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251476 control chromosomes (gnomAD). c.59A>G has been reported in the literature in individuals affected with Glycogen Storage Disease Type Ia (e.g. Seydewitz_2000, Al-Shamsi_2014, Lenzini_2022). These data indicate that the variant is 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 (Shieh_2002). The following publications have been ascertained in the context of this evaluation (PMID: 10612834, 11739393, 24516753, 36613675). ClinVar contains an entry for this variant (Variation ID: 1030625). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 04, 2019

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1

Jul 09, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PS3 -

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;.
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

Other links and lift over

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