rs386833560
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000170.3(GLDC):c.2489C>T(p.Thr830Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,996 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. T830K) has been classified as Pathogenic.
Frequency
Consequence
NM_000170.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLDC | NM_000170.3 | c.2489C>T | p.Thr830Met | missense_variant | 21/25 | ENST00000321612.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLDC | ENST00000321612.8 | c.2489C>T | p.Thr830Met | missense_variant | 21/25 | 1 | NM_000170.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152112Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251478Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135910
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1460884Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 726866
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74304
ClinVar
Submissions by phenotype
Non-ketotic hyperglycinemia Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Translational Omics - GOSgene, University College London | Mar 16, 2018 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 830 of the GLDC protein (p.Thr830Met). This variant is present in population databases (rs386833560, gnomAD 0.03%). This missense change has been observed in individual(s) with non-ketotic hyperglycinemia (PMID: 27362913). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56079). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at