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

2

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]

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
G6PC1NM_000151.4 linkuse as main transcriptc.648G>T p.Leu216= synonymous_variant 5/5 ENST00000253801.7
G6PC1NM_001270397.2 linkuse as main transcriptc.*40G>T 3_prime_UTR_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
G6PC1ENST00000253801.7 linkuse as main transcriptc.648G>T p.Leu216= synonymous_variant 5/51 NM_000151.4 P1P35575-1
G6PC1ENST00000585489.1 linkuse as main transcriptc.*40G>T 3_prime_UTR_variant 4/45
G6PC1ENST00000592383.5 linkuse as main transcriptc.*40G>T 3_prime_UTR_variant 5/52 P35575-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152164
Hom.:
0
Cov.:
32
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:
21
AN:
251236
Hom.:
0
AF XY:
0.0000958
AC XY:
13
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:
57
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.0000399
AC XY:
29
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:
4
AN:
152282
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
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.:
0
Bravo
AF:
0.0000340
Asia WGS
AF:
0.000289
AC:
1
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024This 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 submitterclinical testingRevvity Omics, RevvityJan 19, 2023- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 23, 2016Variant 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 providedliterature onlyOMIMMar 13, 2000- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 28, 2022- -
Pathogenic, no assertion criteria providedclinical testingCounsylJan 02, 2014- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 11, 2019The 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 providedliterature onlyGeneReviews-- -
Likely pathogenic, criteria provided, single submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 18, 2022- -
Pathogenic, criteria provided, single submitterclinical testing3billionMar 22, 2022Synonymous 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 providedclinical testingNatera, Inc.Mar 17, 2017- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 20, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 11, 2024Reported 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.

Other links and lift over

dbSNP: rs80356484; hg19: chr17-41063017; API