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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2023

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;