rs121434369
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000159.4(GCDH):c.1204C>G(p.Arg402Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,792 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R402Q) has been classified as Pathogenic.
Frequency
Consequence
NM_000159.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.1204C>G | p.Arg402Gly | missense_variant | Exon 11 of 12 | ENST00000222214.10 | NP_000150.1 | |
GCDH | NM_013976.5 | c.1204C>G | p.Arg402Gly | missense_variant | Exon 11 of 12 | NP_039663.1 | ||
GCDH | NR_102316.1 | n.1367C>G | non_coding_transcript_exon_variant | Exon 11 of 12 | ||||
GCDH | NR_102317.1 | n.1585C>G | non_coding_transcript_exon_variant | Exon 10 of 11 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461792Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727216
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:1
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 402 of the GCDH protein (p.Arg402Gly). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 15505393). 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 GCDH protein function. This variant disrupts the p.Arg402 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8900227, 10649503, 11073722, 20732827, 28352331, 28438223). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.