17-42911374-T-C

Variant names:

• chr17-42911374-T-C
• rs387906505
• NM_000151.4:c.1022T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_000151.4(G6PC1):​c.1022T>C​(p.Ile341Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I341N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: G6PC1 NM_000151.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.62
• Publications: 13 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Myriad Women’s Health

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 chr17-42911374-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12009.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC1	NM_000151.4	c.1022T>C	p.Ile341Thr	missense_variant	Exon 5 of 5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.*414T>C		3_prime_UTR_variant	Exon 5 of 5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.1022T>C	p.Ile341Thr	missense_variant	Exon 5 of 5	1	NM_000151.4	ENSP00000253801.1
G6PC1	ENST00000585489.1	c.*414T>C		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000466202.1
G6PC1	ENST00000592383.5	c.*414T>C		downstream_gene_variant		2		ENSP00000465958.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.019	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.011	D
Polyphen		0.75	P
Vest4		0.69
MutPred		0.57		Gain of glycosylation at I341 (P = 0.0516);
MVP		0.95
MPC		0.60
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.26
gMVP		0.67

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: rs387906505; hg19: chr17-41063391;