17-42911161-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000151.4(G6PC1):c.809G>T(p.Gly270Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,990 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. G270R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000151.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
G6PC1 | ENST00000253801.7 | c.809G>T | p.Gly270Val | missense_variant | Exon 5 of 5 | 1 | NM_000151.4 | ENSP00000253801.1 | ||
G6PC1 | ENST00000592383.5 | c.*201G>T | 3_prime_UTR_variant | Exon 5 of 5 | 2 | ENSP00000465958.1 | ||||
G6PC1 | ENST00000585489.1 | c.*201G>T | 3_prime_UTR_variant | Exon 4 of 4 | 5 | ENSP00000466202.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251364Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135852
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727246
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74286
ClinVar
Submissions by phenotype
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:10
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Variant summary: G6PC c.809G>T (p.Gly270Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251364 control chromosomes. c.809G>T has been widely reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (example, Lei_1995, Chevalier-Porst_1996, Parvari_1999, Allegrini_2017, Peeks_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete abolishment of Glucose 6-phosphatase activity and accumulation of glycogen in liver (example, Lei_1995, Chevalier-Porst_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
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Experimental studies have shown that this missense change affects G6PC function (PMID: 7573034). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 270 of the G6PC protein (p.Gly270Val). This variant is present in population databases (rs80356483, gnomAD 0.003%). This missense change has been observed in individuals with glycogen storage disease (PMID: 7573034, 8733042, 10234610, 28397058, 28659124). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21063). 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. For these reasons, this variant has been classified as Pathogenic. -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000021063). Different missense changes at the same codon (p.Gly270Arg, p.Gly270Asp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001217274, VCV002039518). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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not provided Pathogenic:1
Published functional studies demonstrate a damaging effect: abolished enzyme activity (Lei et al., 1995; Shieh et al., 2002); Not observed at a significant frequency or in the homozygous state in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 10234610, 28659124, 7573034, 11739393, 28397058) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at