rs104894563
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The ENST00000253801.7(G6PC1):c.883C>T(p.Arg295Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R295H) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000253801.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
G6PC1 | NM_000151.4 | c.883C>T | p.Arg295Cys | missense_variant | 5/5 | ENST00000253801.7 | NP_000142.2 | |
G6PC1 | NM_001270397.2 | c.*275C>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.883C>T | p.Arg295Cys | missense_variant | 5/5 | 1 | NM_000151.4 | ENSP00000253801 | P1 | |
G6PC1 | ENST00000585489.1 | c.*275C>T | 3_prime_UTR_variant | 4/4 | 5 | ENSP00000466202 | ||||
G6PC1 | ENST00000592383.5 | c.*275C>T | 3_prime_UTR_variant | 5/5 | 2 | ENSP00000465958 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251428Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135878
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727248
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
ClinVar
Submissions by phenotype
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:7
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The G6PC c.883C>T (p.Arg295Cys) variant was reported in a compound heterozygous state with a second variant in two individuals with glycogen storage disease (GSD) type I and in five alleles from individuals with the disorder (Lei et al. 1993; Lei et al 1995; Stroppiano et al. 1999; Kozak et al. 2000; Matern et al. 2002; Di Rocco et al. 2008). The variant was absent from a total of 14 healthy control individuals but is reported at a frequency of 0.00002 in the Total population of the Exome Aggregation Consortium. Functional studies by Lei et al. (1993) showed that phosphohydrolase activity was abolished in COS1 cells expressing the p.Arg295Cys variant, while research by Shieh et al. (2002) suggested that the p.Arg295Cys variant could cause misfolding and protein degradation. Based on the evidence, the p.Arg295Cys variant is classified as likely 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, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 18, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 08, 2016 | Variant summary: The G6PC c.883C>T (p.Arg295Cys) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/121408 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). This variant has been reported in numerous GSD1a patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 28, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 295 of the G6PC protein (p.Arg295Cys). This variant is present in population databases (rs104894563, gnomAD 0.007%). This missense change has been observed in individual(s) with glycogen storage disease type la (PMID: 8211187, 10070617, 12373566, 18083610). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.962C>T. ClinVar contains an entry for this variant (Variation ID: 11999). 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. Experimental studies have shown that this missense change affects G6PC function (PMID: 8211187, 11739393). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 22, 1993 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 17, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 22, 2022 | PP4, PM2, PM3, PS3, PS4_moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 13, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at