rs104894566

Positions:

• chr17-42901105-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 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 (★★).

• 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:5
• Conservation: PhyloP100: 7.94

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 12001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC1	NM_000151.4	c.229T>C	p.Trp77Arg	missense_variant, splice_region_variant	1/5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.229T>C	p.Trp77Arg	missense_variant, splice_region_variant	1/5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.229T>C	p.Trp77Arg	missense_variant, splice_region_variant	1/5	1	NM_000151.4	ENSP00000253801	P1
G6PC1	ENST00000592383.5	c.229T>C	p.Trp77Arg	missense_variant, splice_region_variant	1/5	2		ENSP00000465958
G6PC1	ENST00000585489.1	c.229T>C	p.Trp77Arg	missense_variant, splice_region_variant	1/4	5		ENSP00000466202
G6PC1	ENST00000588481.1	n.294T>C		splice_region_variant, non_coding_transcript_exon_variant	1/2	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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000721

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1996	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2021	Variant summary: G6PC c.229T>C (p.Trp77Arg) results in a non-conservative amino acid change located in the phosphatidic acid phosphate type 2/haloperoxidase domain (IPR000326) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251312 control chromosomes. c.229T>C has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (example, Chevalier-Porst_1996, Terzioglu_2001, Miltenberger-Miltenyi_2005, Eminoglu_2013, Quackenbush_2018). These data indicate that the variant is very 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 G6P'ase enzyme activity in vitro in an experimental system of COS-7 cells transfected with mutant constructs (example, Bruni_1999). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 19, 2021	NM_000151.3(G6PC1):c.229T>C(W77R) is a missense variant classified as pathogenic in the context of glycogen storage disease type Ia. W77R has been observed in cases with relevant disease (PMID: 8733042, 11916325, 16435186, 23352793, 29374762). Functional assessments of this variant are available in the literature (PMID: 10738525, 11739393). W77R has not been observed in population frequency databases. In summary, NM_000151.3(G6PC1):c.229T>C(W77R) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2023	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 77 of the G6PC protein (p.Trp77Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GSD1a (PMID: 11916325, 16435186, 23352793, 29374762). ClinVar contains an entry for this variant (Variation ID: 12001). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects G6PC function (PMID: 10738525, 11739393). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.054	D
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-13	.;D;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.97
MutPred		0.93		Loss of MoRF binding (P = 0.1012);Loss of MoRF binding (P = 0.1012);Loss of MoRF binding (P = 0.1012);
MVP		0.97
MPC		0.69
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894566; hg19: chr17-41053122;