chr17-42903947-C-T

Position:

• chr17-42903947-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1 PM2 PM5 PP3 PP5_Very_Strong BP4

The NM_000151.4(G6PC1):​c.247C>T​(p.Arg83Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,611,788 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R83I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: G6PC1 NM_000151.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27 O:1
• Conservation: PhyloP100: 2.67

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 14 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity G6PC1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000151.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• PP5: Variant 17-42903947-C-T is Pathogenic according to our data. Variant chr17-42903947-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42903947-C-T is described in Lovd as [Pathogenic]. Variant chr17-42903947-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-42903947-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.28041). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC1	NM_000151.4	c.247C>T	p.Arg83Cys	missense_variant	2/5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.247C>T	p.Arg83Cys	missense_variant	2/5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.247C>T	p.Arg83Cys	missense_variant	2/5	1	NM_000151.4	ENSP00000253801	P1
G6PC1	ENST00000592383.5	c.247C>T	p.Arg83Cys	missense_variant	2/5	2		ENSP00000465958
G6PC1	ENST00000585489.1	c.247C>T	p.Arg83Cys	missense_variant	2/4	5		ENSP00000466202
G6PC1	ENST00000588481.1	n.312C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152126 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000573 AC: 144 AN: 251452 Hom.: 1 AF XY: 0.000508 AC XY: 69 AN XY: 135900

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000400 AC: 584 AN: 1459662 Hom.: 1 Cov.: 30 AF XY: 0.000409 AC XY: 297 AN XY: 726290

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000298

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152126 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20 AN XY: 74314

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000721

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.000709 Hom.: 1

Bravo AF: 0.000472

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000527 AC: 64

EpiCase AF: 0.000491

EpiControl AF: 0.000889

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:19 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The G6PC c.247C>T (p.Arg83Cys) variant is widely reported in the literature as a pathogenic variant for glycogen storage disease type I. The variant has been described in several studies as the most prevalent variant for this disease in the Ashkenazi Jewish population (Ekstein et al. 2004; Bali et al. 2006; Froissart et al. 2011). Across eight studies of individuals of different ethnic origins with glycogen storage disease type I, the p.Arg83Cys variant was reported in 35% (110/312) of alleles including at least 25 individuals in whom the variant was found in a homozygous state and seven in whom the variant was found in a compound heterozygous state (Lei et al. 1993; Lei et al. 1994; Lei et al. 1995; Parvari et al. 1997; Rake et al. 2000; Seydewitz et al. 2000; Sever et al. 2012; Carlin et al. 2013). All individuals showed significantly reduced or undetectable enzyme activity in liver biopsy samples. No control data were available from these studies, though the variant is reported at a frequency of 0.00090 in the European (non-Finnish) population of the Exome Aggregation Consortium. Transient expression studies of the variant by Lei et al. (1993) demonstrated that the p.Arg83Cys abolishes enzyme activity. Based on the collective evidence, the p.Arg83Cys variant is classified as pathogenic for glycogen storage disease type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 01, 2023	- -
Pathogenic, criteria provided, single submitter	research	Kids Research, The Children's Hospital at Westmead	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.053%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.97). It has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011998). A different missense change at the same codon (p.Arg83His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000038300). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Dec 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 83 of the G6PC protein (p.Arg83Cys). This variant is present in population databases (rs1801175, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with glycogen storage disease (PMID: 7623438, 10834516, 15316959, 18008183, 23312056, 24385852). 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 c.326C>T. ClinVar contains an entry for this variant (Variation ID: 11998). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PC function (PMID: 7744838). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000151.3:c.247C>T is also known as c.326C>T in the literature. NM_000151.3:c.247C>T in the G6PC gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been reported to segregate with glycogen storage disease type 1a in a single family (PMID: 8211187) and has been reported as homozygous or in combination with another G6PC variant in individuals affected with glycogen storage disease type 1A (PMID: 23312056). Ekstein et al reported 30 Glycogen storage disease type Ia patient in Ashkenazi Jewish origin. All of them are homozygous of this variant (PMID: 15316959). Experimental studies have shown that this missense change severely reduces enzyme activity of the protein encoded by G6PC (PMID: 7744838). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4; PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000151.3(G6PC):c.247C>T(R83C) is classified as pathogenic in the context of glycogen storage disease type Ia. Sources cited for classification include the following: PMID: 10874313, 12093795, 8734807, 7814621, 15316959, 24082139, 12373566, and 9332655. Classification of NM_000151.3(G6PC):c.247C>T(R83C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2016	Variant summary: The G6PC c.247C>T (p.Arg83Cys) variant involves the alteration of a conserved nucleotide resulting in a replacement of and Arginine with a Cystein located in the conserved phosphatase signature motif of G6PC. Mutations of the phosphatase active site residues are known to be clinically relevant; they predispose individuals to Glycogen Storage Disease (Clinvar, HGMD). Consistently, 5/5 in silico tools predict this variant to be deleterious. The variant was found in 64/121294 control chromosomes (1 homozygote) at a frequency of 0.0005276, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). It was reported in several GSD patients in either homozygosity or in compound heterozygosity with other pathogenic variant indicating a disease causing impact. A functional study demonstrated the variant to result in complete inactivation of the enzyme, confirming the importance of an intact Arg83 residue in G6Pase catalysis and further supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as a Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 30, 2004	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Oct 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Dec 08, 2021	This variant was previously reported in patients with glycogen storage disease in homozygous or compound heterozygous state and reported to segregate with glycogen storage disease type 1a in a family [PMID: 8211187, 23312056, 18008183, 15316959, 15316959, 7623438, 24385852, 10834516]. Functional studies suggested that this variant reduces enzyme activity [PMID: 7744838, 11739393, 18449899]. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2022	Published functional studies demonstrate loss of glucose-6-phosphatase enzyme activity (Shieh et al., 2002; Chou et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12713862, 23312056, 8734807, 25333069, 24082139, 8211187, 18449899, 7623438, 15316959, 11739393, 28360385, 28397058, 29365308, 9664612, 30609409, 30202406, 31980526, 32313153, 33224545, 34426522, 34093448, 34258141, 31589614, 33763395, 33101979, 33258288, 31319225) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	G6PC1: PM3:Very Strong, PM1, PM5, PP4:Moderate, PS3:Moderate, PM2:Supporting, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 29, 2023	PS3, PS4_moderate, PM1, PM2, PP1, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2018	- -

not specified Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 03, 2022	The c.247C>T (p.R83C) alteration is located in exon 2 (coding exon 2) of the G6PC gene. This alteration results from a C to T substitution at nucleotide position 247, causing the arginine (R) at amino acid position 83 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.05% (151/282828) total alleles studied. The highest observed frequency was 0.66% (68/10370) of Ashkenazi Jewish alleles. This alteration has been detected in the homozygous state, and in conjunction with other pathogenic mutations in G6PC1, in multiple individuals with G6PC1-related glycogen storage disease type I (Peeks, 2017; Lei, 1994; Düzenli, 2019; Lei, 1993; Saneifard, 2020; Riley, 2020; Muzetti, 2021; Fang, 2021). It has also been found to segregate in affected individuals in the same family (Carvès, 2003). Another alteration at the same codon, p.R83H (c.248G>A), has been described in individuals with G6PC1-related glycogen storage disease type I (Lei, 1995; Fang, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -

Glycogen storage disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 06, 2016

The p.Arg83Cys variant in G6PC is the most frequent pathogenic variant implicate d in Glycogen storage disease type I in the Ashkenazi Jewish population (Parvari 1997, Lei 1995, Ekstein 2004). This variant has also been identified 0.09% (60/ 66,646) of European chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs1801175). In vitro functional studies also p rovide evidence that the p.Arg83Cys variant may impact protein function (Lei 199 3). In summary, this variant meets our criteria to be classified as pathogenic f or Glycogen storage disease type I in an autosomal recessive manner based upon i ts identification in patients and functional impact. -

Hypoglycemia;C0349588:Short stature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;H;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.9	.;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.97
MVP		0.98
MPC		0.93
ClinPred		0.30	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs1801175; hg19: chr17-41055964;