17-42911000-G-T

Position:

chr17-42911000-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000151.4(G6PC1):c.648G>T(p.Leu216=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L216L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

G6PC1
NM_000151.4 synonymous

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 0.454

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-42911000-G-T is Pathogenic according to our data. Variant chr17-42911000-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC1	NM_000151.4 linkuse as main transcript	c.648G>T	p.Leu216=	synonymous_variant	5/5	ENST00000253801.7
G6PC1	NM_001270397.2 linkuse as main transcript	c.*40G>T		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC1	ENST00000253801.7 linkuse as main transcript	c.648G>T	p.Leu216=	synonymous_variant	5/5	1	NM_000151.4	P1	P35575-1
G6PC1	ENST00000585489.1 linkuse as main transcript	c.*40G>T		3_prime_UTR_variant	4/4	5
G6PC1	ENST00000592383.5 linkuse as main transcript	c.*40G>T		3_prime_UTR_variant	5/5	2			P35575-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152164

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:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251236

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00114

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00144

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000340

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:11Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change affects codon 216 of the G6PC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the G6PC protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs80356484, gnomAD 0.1%). This variant has been observed in individual(s) with glycogen storage disease type 1 (PMID: 7668282, 10797430, 23000067, 23486339, 24980439; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as g727t. ClinVar contains an entry for this variant (Variation ID: 12003). Studies have shown that this variant results in partial deletion of exon 5 and introduces a new termination codon (PMID: 7668282, 10748407). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 23, 2016	Variant summary: The G6PC c.648G>T (p.Leu216Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant may strengthen a cryptic 3' splicing acceptor site in exon 5. ESE finder predicts that this variant may create a novel SRp40 binding site. These predictions have been confirmed by at least one functional study (Kajihara_1995), showing this variant leads to a deletion of the front 91 nt of exon 5 in the patient's cDNA and this deletion results in a premature stop codon. This variant was found in 11/121428 control chromosomes at a frequency of 0.0000906, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). This variant has been reported as the most common pathogenic variant in GSD1a patients in East Asia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 13, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 28, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 11, 2019	The G6PC c.648G>T (p.Leu216Leu) synonymous variant is an established pathogenic variant that occurs in approximately 91% of Japanese glucogen storage disease type 1 (GSD1) alleles, 75% of Korean GSD1 alleles, and 54% of Chinese GSD1 alleles (Chou et al. 2008; Froissart et al. 2011; Bali 2013). Across a selection of available literature, the p.Leu216Leu variant has been reported in at least 55 individuals with glycogen storage disease type 1, including 47 in a homozygous state and eight in a compound heterozygous state (Kajihara et al. 1995; Akanuma et al. 2000). The p.Leu216Leu variant is reported at a frequency of 0.001271 in the East Asian population in the Exome Aggregation Consortium. The variant, although far from a splice junction, produces an aberrant transcript that eliminates 91 nucleotides and alters the reading frame, creating a premature termination at Tyr202 (Kajihara et al. 1995; Akanuma et al. 2000; Bali et al. 2013). Based on the collective evidence, the p.Leu216 variant is classified as pathogenic for glycogen storage disease type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Synonymous variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 7668282, PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012003, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000873). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 23000067, 11851840). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2024	Reported as a common pathogenic variant in association with GSD1a among individuals of Japanese, Korean, and Chinese backgrounds (PMID: 18449899); Published functional studies demonstrate this variant results in a deletion of 91 base pairs from exon 5 (PMID: 7668282, 10748407); Also known as G727T using alternate nomenclature; This variant is associated with the following publications: (PMID: 10797430, 24980439, 31109299, 32046761, 32924126, 10748407, 33763395, 36160031, 36452356, 36595986, 36167523, 35314707, 35257483, 35783312, 18449899, 37788110, 7668282) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

5.4

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over