rs104894571
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5
The NM_000151.4(G6PC1):c.497T>C(p.Val166Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V166G) has been classified as Pathogenic.
Frequency
Consequence
NM_000151.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
G6PC1 | NM_000151.4 | c.497T>C | p.Val166Ala | missense_variant | 4/5 | ENST00000253801.7 | |
G6PC1 | NM_001270397.2 | c.420T>C | p.Cys140= | synonymous_variant | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
G6PC1 | ENST00000253801.7 | c.497T>C | p.Val166Ala | missense_variant | 4/5 | 1 | NM_000151.4 | P1 | |
G6PC1 | ENST00000592383.5 | c.420T>C | p.Cys140= | synonymous_variant | 4/5 | 2 | |||
G6PC1 | ENST00000585489.1 | c.447-1562T>C | intron_variant | 5 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 09, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 25, 2023 | This missense change has been observed in individual(s) with glycogen storage disease type 1a (PMID: 10834516, 10874313). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 556681). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 166 of the G6PC protein (p.Val166Ala). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val166Gly amino acid residue in G6PC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7623438). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects G6PC function (PMID: 11739393). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 13, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at