chr17-42909323-G-T

Variant names:

• chr17-42909323-G-T
• rs1189630738
• NM_000151.4:c.467G>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000151.4(G6PC1):​c.467G>T​(p.Trp156Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,736 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001222587: Experimental studies have shown that this missense change affects G6PC function (PMID:11739393)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: G6PC1 NM_000151.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.10
• Publications: 8 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: G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• glycogen storage disease I

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001222587: Experimental studies have shown that this missense change affects G6PC function (PMID: 11739393).; SCV003934316: The variant results in <5% of normal phosphohydrolase activity. PMID:11739393, PMID:28397058, PMID:35811762
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 0.2658 (below the threshold of 3.09). Trascript score misZ: 1.1659 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease due to glucose-6-phosphatase deficiency type IA, glycogen storage disease I.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 17-42909323-G-T is Pathogenic according to our data. Variant chr17-42909323-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 557154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000151.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC1	NM_000151.4	MANE Select	c.467G>T	p.Trp156Leu	missense	Exon 4 of 5	NP_000142.2	P35575-1
	G6PC1	NM_001270397.2		c.390G>T	p.Val130Val	synonymous	Exon 4 of 5	NP_001257326.1	P35575-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC1	ENST00000253801.7	TSL:1 MANE Select	c.467G>T	p.Trp156Leu	missense	Exon 4 of 5	ENSP00000253801.1	P35575-1
	G6PC1	ENST00000887113.1		c.464G>T	p.Trp155Leu	missense	Exon 4 of 5	ENSP00000557172.1
	G6PC1	ENST00000887112.1		c.390G>T	p.Val130Val	synonymous	Exon 4 of 5	ENSP00000557171.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251492 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727198

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111868

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000740 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.55	T
PhyloP100		7.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.086	T
Polyphen		0.34	B
Vest4		0.79
MVP		0.85
MPC		0.91
ClinPred		0.94	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.89
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs1189630738; hg19: chr17-41061340;