rs386833589
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000170.3(GLDC):c.847G>C(p.Ala283Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,536 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. A283G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000170.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLDC | NM_000170.3 | c.847G>C | p.Ala283Pro | missense_variant | 6/25 | ENST00000321612.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLDC | ENST00000321612.8 | c.847G>C | p.Ala283Pro | missense_variant | 6/25 | 1 | NM_000170.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251464Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135902
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1460418Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 726540
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74302
ClinVar
Submissions by phenotype
Non-ketotic hyperglycinemia Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 283 of the GLDC protein (p.Ala283Pro). This variant is present in population databases (rs386833589, gnomAD 0.0009%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 26179960, 27362913). ClinVar contains an entry for this variant (Variation ID: 56106). 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 GLDC protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLDC function (PMID: 26179960). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 23, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at