17-42900926-A-ATTACCTCCAGGTGAAT

Variant names:

• chr17-42900926-A-ATTACCTCCAGGTGAAT
• rs1555558920
• NM_000151.4:c.52_67dupTACCTCCAGGTGAATT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000151.4(G6PC1):​c.52_67dupTACCTCCAGGTGAATT​(p.Tyr23LeufsTer43) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y23Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: G6PC1 NM_000151.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.151
• Publications: 0 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 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 145 pathogenic variants in the truncated region.
• PP5: Variant 17-42900926-A-ATTACCTCCAGGTGAAT is Pathogenic according to our data. Variant chr17-42900926-A-ATTACCTCCAGGTGAAT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550812.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC1	NM_000151.4	c.52_67dupTACCTCCAGGTGAATT	p.Tyr23LeufsTer43	frameshift_variant	Exon 1 of 5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.52_67dupTACCTCCAGGTGAATT	p.Tyr23LeufsTer43	frameshift_variant	Exon 1 of 5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.52_67dupTACCTCCAGGTGAATT	p.Tyr23LeufsTer43	frameshift_variant	Exon 1 of 5	1	NM_000151.4	ENSP00000253801.1
G6PC1	ENST00000592383.5	c.52_67dupTACCTCCAGGTGAATT	p.Tyr23LeufsTer43	frameshift_variant	Exon 1 of 5	2		ENSP00000465958.1
G6PC1	ENST00000585489.1	c.52_67dupTACCTCCAGGTGAATT	p.Tyr23LeufsTer43	frameshift_variant	Exon 1 of 4	5		ENSP00000466202.1
G6PC1	ENST00000588481.1	n.117_132dupTACCTCCAGGTGAATT		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Oct 10, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.15

Splicing

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

Other links and lift over

dbSNP: rs1555558920; hg19: chr17-41052943;