rs1555560128

Positions:

• chr17-42911026-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000151.4(G6PC1):​c.674T>C​(p.Leu225Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: G6PC1 NM_000151.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.18

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 17-42911026-T-C is Pathogenic according to our data. Variant chr17-42911026-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550615.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC1	NM_000151.4	c.674T>C	p.Leu225Pro	missense_variant	5/5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.*66T>C		3_prime_UTR_variant	5/5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.674T>C	p.Leu225Pro	missense_variant	5/5	1	NM_000151.4	ENSP00000253801	P1
G6PC1	ENST00000585489.1	c.*66T>C		3_prime_UTR_variant	4/4	5		ENSP00000466202
G6PC1	ENST00000592383.5	c.*66T>C		3_prime_UTR_variant	5/5	2		ENSP00000465958

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 13, 2022	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 225 of the G6PC protein (p.Leu225Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 20509832, 33763395). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550615). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PC protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 03, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.87
Sift	Benign	0.070	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.95
MutPred		0.70		Loss of stability (P = 0.0232);
MVP		0.97
MPC		1.0
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555560128; hg19: chr17-41063043;