chr9-6533097-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000170.3(GLDC):c.2983G>A(p.Asp995Asn) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D995Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_000170.3 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 |
---|---|---|---|---|---|---|---|
GLDC | NM_000170.3 | c.2983G>A | p.Asp995Asn | missense_variant | 25/25 | ENST00000321612.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLDC | ENST00000321612.8 | c.2983G>A | p.Asp995Asn | missense_variant | 25/25 | 1 | NM_000170.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Non-ketotic hyperglycinemia Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 24, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 08, 2021 | 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 sequence change replaces aspartic acid with asparagine at codon 995 of the GLDC protein (p.Asp995Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with nonketotic hyperglycinemia (PMID: 27362913). ClinVar contains an entry for this variant (Variation ID: 554525). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at