17-42900930-C-A

Variant names:

• chr17-42900930-C-A
• rs1414234636
• NM_000151.4:c.54C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000151.4(G6PC1):​c.54C>A​(p.Tyr18*) variant causes a stop gained change involving the alteration of a non-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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: G6PC1 NM_000151.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.31
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease due to glucose-6-phosphatase deficiency type IA

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 148 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-42900930-C-A is Pathogenic according to our data. Variant chr17-42900930-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1682476.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC1	NM_000151.4	c.54C>A	p.Tyr18*	stop_gained	Exon 1 of 5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.54C>A	p.Tyr18*	stop_gained	Exon 1 of 5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.54C>A	p.Tyr18*	stop_gained	Exon 1 of 5	1	NM_000151.4	ENSP00000253801.1
G6PC1	ENST00000592383.5	c.54C>A	p.Tyr18*	stop_gained	Exon 1 of 5	2		ENSP00000465958.1
G6PC1	ENST00000585489.1	c.54C>A	p.Tyr18*	stop_gained	Exon 1 of 4	5		ENSP00000466202.1
G6PC1	ENST00000588481.1	n.119C>A		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: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Aug 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with G6PC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr18*) in the G6PC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in G6PC are known to be pathogenic (PMID: 8182131). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		1.3
Vest4		0.80
GERP RS		-0.41
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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

Other links and lift over

dbSNP: rs1414234636; hg19: chr17-41052947;