rs1057517008
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000151.4(G6PC1):āc.161A>Cā(p.Gln54Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_000151.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
G6PC1 | NM_000151.4 | c.161A>C | p.Gln54Pro | missense_variant | 1/5 | ENST00000253801.7 | |
G6PC1 | NM_001270397.2 | c.161A>C | p.Gln54Pro | missense_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
G6PC1 | ENST00000253801.7 | c.161A>C | p.Gln54Pro | missense_variant | 1/5 | 1 | NM_000151.4 | P1 | |
G6PC1 | ENST00000592383.5 | c.161A>C | p.Gln54Pro | missense_variant | 1/5 | 2 | |||
G6PC1 | ENST00000585489.1 | c.161A>C | p.Gln54Pro | missense_variant | 1/4 | 5 | |||
G6PC1 | ENST00000588481.1 | n.226A>C | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727246
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2023 | This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 54 of the G6PC protein (p.Gln54Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with glycogen storage disease type 1a (PMID: 10447271, 15542400). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 371101). 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 80%. Experimental studies have shown that this missense change affects G6PC function (PMID: 11739393). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 27, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 07, 2019 | Variant summary: G6PC c.161A>C (p.Gln54Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251444 control chromosomes (gnomAD). The variant, c.161A>C, has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (Trioche_1999, Angaroni_2004). These data indicate that the variant is very likely to be associated with disease. One publication, Shieh_2002, reports G6Pase activity of this residual variant remained <10% of normal activity. One ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at