17-42911000-G-T

Position:

• chr17-42911000-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: G6PC1 NM_000151.4 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 0.454

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 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	Protein	UniProt
G6PC1	NM_000151.4	c.648G>T	p.Leu216=	synonymous_variant	5/5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.*40G>T		3_prime_UTR_variant	5/5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.648G>T	p.Leu216=	synonymous_variant	5/5	1	NM_000151.4	ENSP00000253801	P1
G6PC1	ENST00000585489.1	c.*40G>T		3_prime_UTR_variant	4/4	5		ENSP00000466202
G6PC1	ENST00000592383.5	c.*40G>T		3_prime_UTR_variant	5/5	2		ENSP00000465958

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 32

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

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

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

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:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:11 Other: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

Other links and lift over

dbSNP: rs80356484; hg19: chr17-41063017;