Genetic Variant G6PC1:p.Arg83Cys (chr17-42903947-C-T) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 18P and 1B. PS3PM1PM5PP2PP3PP5_Very_StrongBP4

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 (★★). ClinVar reports functional evidence for this variant: "SCV000402976: Transient expression studies of the variant by Lei et al. (1993) demonstrated that the p.Arg83Cys abolishes enzyme activity." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R83H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00040 ( 1 hom. )

Consequence

G6PC1
NM_000151.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:30O:1

Conservation

PhyloP100: 2.67

Publications

118 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: G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
glycogen storage disease I
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

G6PC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000402976: Transient expression studies of the variant by Lei et al. (1993) demonstrated that the p.Arg83Cys abolishes enzyme activity.; SCV000658103: Experimental studies have shown that this missense change affects G6PC function (PMID: 7744838).; SCV000695636: 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.; SCV001142473: Experimental studies have shown that this missense change severely reduces enzyme activity of the protein encoded by G6PC (PMID: 7744838).; SCV005088759: Functional studies suggested that this variant reduces enzyme activity [PMID: 7744838, 11739393, 18449899].; SCV005875332: Functional analyses have shown the variant protein levels are significantly reduced compared to wild type and the variant protein shows abnormal localization (Plona 2021). PMID: 34258141; SCV000712202: "In vitro functional studies also provide evidence that the p.Arg83Cys variant may impact protein function (Lei 1993)."; SCV000520992: Published functional studies demonstrate loss of glucose-6-phosphatase enzyme activity (Shieh et al., 2002; Chou et al., 2008); SCV001246604: PS3:Supporting

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000151.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-42903948-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 0.2658 (below the threshold of 3.09). Trascript score misZ: 1.1659 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease due to glucose-6-phosphatase deficiency type IA, glycogen storage disease I.

PP3

Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL, 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 VariationId is 11998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.28041). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000151.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC1	NM_000151.4	MANE Select	c.247C>T	p.Arg83Cys	missense	Exon 2 of 5	NP_000142.2	P35575-1
	G6PC1	NM_001270397.2		c.247C>T	p.Arg83Cys	missense	Exon 2 of 5	NP_001257326.1	P35575-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
G6PC1	ENST00000253801.7	TSL:1 MANE Select	c.247C>T	p.Arg83Cys	missense	Exon 2 of 5	ENSP00000253801.1	P35575-1
G6PC1	ENST00000887113.1		c.244C>T	p.Arg82Cys	missense	Exon 2 of 5	ENSP00000557172.1
G6PC1	ENST00000887112.1		c.247C>T	p.Arg83Cys	missense	Exon 2 of 5	ENSP00000557171.1

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000573

AC:

144

AN:

251452

AF XY:

0.000508

show subpopulations

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 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.:

Cov.:

AF XY:

0.000409

AC XY:

297

AN XY:

726290

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33444

American (AMR)

AF:

0.000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00708

AC:

185

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000298

AC:

331

AN:

1109978

Other (OTH)

AF:

0.000663

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000348

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.000721

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68026

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000546

Hom.:

Bravo

AF:

0.000472

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000527

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000889

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA (22)

not provided (4)

not specified (2)

Glycogen storage disease (1)

Glycogen storage disease, type I (1)

Hypoglycemia;C0349588:Short stature (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.28

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.5

PhyloP100

2.7

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-6.9

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MVP

0.98

MPC

0.93

ClinPred

0.30

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.98

Mutation Taster

=14/86

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over