17-42911369-TGTCATCCCCT-TA

Variant names:

• chr17-42911370-GTCATCCCCT-A
• rs1555560204
• NM_000151.4:c.1018_1027delGTCATCCCCTinsA

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The NM_000151.4(G6PC1):​c.1018_1027delGTCATCCCCTinsA​(p.Val340_Tyr343delinsAsn) variant causes a missense, disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: G6PC1 NM_000151.4 missense, disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.62

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 9 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity G6PC1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000151.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000151.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-42911370-GTCATCCCCT-A is Pathogenic according to our data. Variant chr17-42911370-GTCATCCCCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 477018.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.1018_1027delGTCATCCCCTinsA	p.Val340_Tyr343delinsAsn	missense_variant, disruptive_inframe_deletion	Exon 5 of 5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.*410_*419delGTCATCCCCTinsA		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.1018_1027delGTCATCCCCTinsA	p.Val340_Tyr343delinsAsn	missense_variant, disruptive_inframe_deletion	Exon 5 of 5	1	NM_000151.4	ENSP00000253801.1
G6PC1	ENST00000585489.1	c.*410_*419delGTCATCCCCTinsA		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000466202.1
G6PC1	ENST00000592383.5	c.*410_*419delGTCATCCCCTinsA		downstream_gene_variant		2		ENSP00000465958.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: 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

Jul 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the G6PC protein in which other variant(s) (p.Ile341Asn) have been determined to be pathogenic (PMID: 9001800, 11161844, 11739393, 24980439). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with G6PC-related conditions. This variant, c.1018_1027delinsA, is a complex sequence change that results in the deletion of 4 amino acids of G6PC protein and insertion of 1 amino acid(s) in the G6PC protein (p.Val340_Tyr343delinsAsn). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555560204; hg19: chr17-41063387;