rs1801175

Variant names:

• chr17-42903947-C-A
• NM_000151.4:c.247C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-42903947-C-A
• chr17-42903947-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000151.4(G6PC1):​c.247C>A​(p.Arg83Ser) variant causes a missense 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R83I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: G6PC1 NM_000151.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.67

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 12 ACMG points.

• PM1: In a topological_domain Lumenal (size 35) in uniprot entity G6PC1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000151.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-42903947-C-A is Pathogenic according to our data. Variant chr17-42903947-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2581673.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.247C>A	p.Arg83Ser	missense_variant	Exon 2 of 5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.247C>A	p.Arg83Ser	missense_variant	Exon 2 of 5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.247C>A	p.Arg83Ser	missense_variant	Exon 2 of 5	1	NM_000151.4	ENSP00000253801.1
G6PC1	ENST00000592383.5	c.247C>A	p.Arg83Ser	missense_variant	Exon 2 of 5	2		ENSP00000465958.1
G6PC1	ENST00000585489.1	c.247C>A	p.Arg83Ser	missense_variant	Exon 2 of 4	5		ENSP00000466202.1
G6PC1	ENST00000588481.1	n.312C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely 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 02, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: G6PC1 (also known as G6PC) c.247C>A (p.Arg83Ser) results in a non-conservative amino acid change located in the Phosphatidic acid phosphatase 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 282828 control chromosomes (gnomAD). To our knowledge, no occurrence of c.247C>A in individuals affected with Glycogen Storage Disease Type Ia has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Lei_1995). In addition, other missense variants in the same residue (R83C, R83H) have been reported in the Human Gene Mutation Database in association with Glycogen Storage Disease Type Ia and classified as pathogenic in our lab. The following publication have been ascertained in the context of this evaluation (PMID: 7744838). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.5	H;H;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.4	.;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.96
MutPred		0.92		Loss of MoRF binding (P = 0.0183);Loss of MoRF binding (P = 0.0183);Loss of MoRF binding (P = 0.0183);
MVP		0.99
MPC		0.85
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-41055964;