rs104894569

Positions:

• chr17-42909407-G-A
• chr17-42909407-G-T

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.551G>A​(p.Gly184Glu) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: G6PC1 NM_000151.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.27

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, 0.993
• PP5: Variant 17-42909407-G-A is Pathogenic according to our data. Variant chr17-42909407-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12007.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC1	NM_000151.4	c.551G>A	p.Gly184Glu	missense_variant	4/5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.474G>A	p.Trp158Ter	stop_gained	4/5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.551G>A	p.Gly184Glu	missense_variant	4/5	1	NM_000151.4	ENSP00000253801	P1
G6PC1	ENST00000592383.5	c.474G>A	p.Trp158Ter	stop_gained	4/5	2		ENSP00000465958
G6PC1	ENST00000585489.1	c.447-1508G>A		intron_variant		5		ENSP00000466202

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.86	P
Vest4		0.99
MutPred		0.94		Loss of catalytic residue at A183 (P = 0.0339);
MVP		0.99
MPC		0.87
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.97

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: rs104894569; hg19: chr17-41061424; COSMIC: COSV99520982;