rs1406713104
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000170.3(GLDC):c.2980G>A(p.Gly994Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,611,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G994G) has been classified as Likely benign.
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.2980G>A | p.Gly994Arg | missense_variant | 25/25 | ENST00000321612.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLDC | ENST00000321612.8 | c.2980G>A | p.Gly994Arg | missense_variant | 25/25 | 1 | NM_000170.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152084Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1459124Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726164
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152084Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74276
ClinVar
Submissions by phenotype
Non-ketotic hyperglycinemia Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 01, 2023 | Variant summary: GLDC c.2980G>A (p.Gly994Arg) 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 was absent in 251454 control chromosomes. c.2980G>A has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (Coughlin_2017, Swanson_2015), and observed to segregate with disease. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function showed undetectable GCS P-protein activity compared to Wildtype (Bravo-Alonso_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28244183, 27362913, 26179960). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 994 of the GLDC protein (p.Gly994Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with nonketotic hyperglycinemia (PMID: 26179960, 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: 550058). 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: 28244183). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 26, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at