rs80356486

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_000151.4(G6PC1):c.980_982delTCT(p.Phe327del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

G6PC1
NM_000151.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.96

Publications

9 publications found

Variant links:

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

G6PC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain 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. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 17-42911329-CCTT-C is Pathogenic according to our data. Variant chr17-42911329-CCTT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 371388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC1	NM_000151.4 link	c.980_982delTCT	p.Phe327del	disruptive_inframe_deletion	Exon 5 of 5	ENST00000253801.7	NP_000142.2	P35575-1
G6PC1	NM_001270397.2 link	c.372_374delTCT		3_prime_UTR_variant	Exon 5 of 5		NP_001257326.1	P35575-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
G6PC1	ENST00000253801.7 link	c.980_982delTCT	p.Phe327del	disruptive_inframe_deletion	Exon 5 of 5	1	NM_000151.4	ENSP00000253801.1	P35575-1
G6PC1	ENST00000592383.5 link	c.372_374delTCT		splice_region_variant	Exon 5 of 5	2		ENSP00000465958.1	P35575-2
G6PC1	ENST00000592383.5 link	c.372_374delTCT		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000465958.1	P35575-2
G6PC1	ENST00000585489.1 link	c.372_374delTCT		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000466202.1	K7ELS6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251410

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461892

Hom.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:6

Mar 17, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 27, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2016

National Center for Biotechnology Information, National Institutes of Health

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.980_982del, results in the deletion of 1 amino acid(s) of the G6PC protein (p.Phe327del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs770928376, gnomAD 0.002%). This variant has been observed in individual(s) with glycogen storage disease (PMID: 7814621, 10834516, 11739393). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1057delTTC or delta F327. ClinVar contains an entry for this variant (Variation ID: 371388). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects G6PC function (PMID: 7814621, 11739393). For these reasons, this variant has been classified as Pathogenic. -

Apr 02, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: G6PC c.980_982delTCT (p.Phe327del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4e-06 in 251410 control chromosomes (gnomAD). c.980_982delTCT (p.Phe327del) has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with Glycogen Storage Disease Type Ia (e.g. Lei_1995, Kishnani_2009). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was found to have very low or no enzymatic activity (e.g. Lei_1995, Shieh_2002). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 14, 2016

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

8.0

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over