rs142967670
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000159.4(GCDH):c.262C>A(p.Arg88Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000039 in 1,614,102 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. R88C) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.262C>A | p.Arg88Ser | missense_variant | 4/12 | ENST00000222214.10 | |
GCDH | NM_013976.5 | c.262C>A | p.Arg88Ser | missense_variant | 4/12 | ||
GCDH | NR_102316.1 | n.370C>A | non_coding_transcript_exon_variant | 4/12 | |||
GCDH | NR_102317.1 | n.678C>A | non_coding_transcript_exon_variant | 3/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCDH | ENST00000222214.10 | c.262C>A | p.Arg88Ser | missense_variant | 4/12 | 1 | NM_000159.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251424Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135900
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.0000371 AC XY: 27AN XY: 727248
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 10, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2023 | This variant disrupts the p.Arg88 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8900227, 23395213, 24332224, 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCDH protein function. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 88 of the GCDH protein (p.Arg88Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with glutaric aciduria, type I (PMID: 27397597; Invitae). ClinVar contains an entry for this variant (Variation ID: 529444). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 16, 2023 | Variant summary: GCDH c.262C>A (p.Arg88Ser) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251424 control chromosomes (gnomAD). c.262C>A has been reported in the literature in an individual affected with Glutaric Acidemia Type 1 (example: Schillaci_2016). Variants at the same codon position as the variant of interest but causing different amino acid changes (i.e. c.262C>T, p.Arg88Cys, classified pathogenic in our internal database; c.263G>A, p.Arg88His) have been reported in multiple affected individuals (Schmiesing_2017, Wang_2014). Schmiesing et al. (2017) carried out functional assessment of the p.Arg88Cys and other variants resulting in different amino acid substitutions at position 88 of the protein sequence, and concluded that Arg88 is essential for preserving mitochondrial architecture and GCDH activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at