rs104894566

Variant names:

• chr17-42901105-T-C
• rs104894566
• NM_000151.4:c.229T>C

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000151.4(G6PC1):​c.229T>C​(p.Trp77Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001201510: Experimental studies have shown that this missense change affects G6PC function (PMID:10738525, 11739393)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: G6PC1 NM_000151.4 missense, splice_region
• Scores: Splicing: ADA: 0.8395
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.94
• Publications: 12 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 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001201510: Experimental studies have shown that this missense change affects G6PC function (PMID: 10738525, 11739393).; SCV001774622: The most pronounced variant effect results in <10% of normal G6P'ase enzyme activity in vitro in an experimental system of COS-7 cells transfected with mutant constructs (example, Bruni_1999).; SCV002060372: Functional assessments of this variant are available in the literature (PMID: 10738525, 11739393).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000151.4
• 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, 0.966
• PP5: Variant 17-42901105-T-C is Pathogenic according to our data. Variant chr17-42901105-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 12001.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.229T>C	p.Trp77Arg	missense splice_region	Exon 1 of 5	NP_000142.2	P35575-1
	G6PC1	NM_001270397.2		c.229T>C	p.Trp77Arg	missense splice_region	Exon 1 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.229T>C	p.Trp77Arg	missense splice_region	Exon 1 of 5	ENSP00000253801.1	P35575-1
	G6PC1	ENST00000887112.1		c.229T>C	p.Trp77Arg	missense splice_region	Exon 1 of 5	ENSP00000557171.1
	G6PC1	ENST00000592383.5	TSL:2	c.229T>C	p.Trp77Arg	missense splice_region	Exon 1 of 5	ENSP00000465958.1	P35575-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458818 Hom.: 0 Cov.: 30 AF XY: 0.00000964 AC XY: 7 AN XY: 725922

African (AFR) AF: 0.0000299 AC: 1 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109210

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000198 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA (5)
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.054	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.93		Loss of MoRF binding (P = 0.1012)
MVP		0.97
MPC		0.69
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		0.074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.98
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Pathogenic	0.88
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: rs104894566; hg19: chr17-41053122;