rs764608975
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000159.4(GCDH):c.1148G>A(p.Arg383His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,864 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. R383C) has been classified as Pathogenic.
Frequency
Consequence
NM_000159.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.1148G>A | p.Arg383His | missense_variant | Exon 11 of 12 | ENST00000222214.10 | NP_000150.1 | |
GCDH | NM_013976.5 | c.1148G>A | p.Arg383His | missense_variant | Exon 11 of 12 | NP_039663.1 | ||
GCDH | NR_102316.1 | n.1311G>A | non_coding_transcript_exon_variant | Exon 11 of 12 | ||||
GCDH | NR_102317.1 | n.1529G>A | non_coding_transcript_exon_variant | Exon 10 of 11 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152082Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251450Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135912
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461782Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727192
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152082Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74290
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:4Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 383 of the GCDH protein (p.Arg383His). This variant is present in population databases (rs764608975, gnomAD 0.01%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 9711871, 33015233, 33578440). ClinVar contains an entry for this variant (Variation ID: 555739). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg383 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15505393, 28438223, 30298489). 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. -
- -
- -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.89 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GCDH related disorder (PMID: 9711871). Different missense changes at the same codon (p.Arg383Cys, p.Arg383Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000188852 /PMID: 30203563, 9711871). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Variant summary: GCDH c.1148G>A (p.Arg383His) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal (IPR009075) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251450 control chromosomes. c.1148G>A has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (Kilavuz_2021, Ulmanova_2020, Goodman_1998). Additionally, other variants affecting the same codon (p.R383C (classified as pathogenic/likely pathogenic in ClinVar) and p.R383S) have been observed in patients with Glutaric Acidemia Type I (e.g. PMID: 33578440, 30203563) supporting functional importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9711871, 33578440, 33015233). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at