rs775606471
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000159.4(GCDH):c.881G>A(p.Arg294Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,104 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. R294P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000159.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.881G>A | p.Arg294Gln | missense_variant | 9/12 | ENST00000222214.10 | NP_000150.1 | |
GCDH | NM_013976.5 | c.881G>A | p.Arg294Gln | missense_variant | 9/12 | NP_039663.1 | ||
GCDH | NR_102316.1 | n.1044G>A | non_coding_transcript_exon_variant | 9/12 | ||||
GCDH | NR_102317.1 | n.1262G>A | non_coding_transcript_exon_variant | 8/11 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250556Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135588
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1460886Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26AN XY: 726782
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74366
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 22, 2022 | Variant summary: GCDH c.881G>A (p.Arg294Gln) results in a conservative amino acid change in 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 1.2e-05 in 250556 control chromosomes. c.881G>A has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence and showed that GCDH activity was not detected in fibroblasts from the patient with homozygous R294Q. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 294 of the GCDH protein (p.Arg294Gln). This variant is present in population databases (rs775606471, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 15505393, 29665094). ClinVar contains an entry for this variant (Variation ID: 859875). 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.Arg294 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9600243, 15505393, 25762492, 29201125; Invitae). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital | - | PM2_P+PM3_S+PP3+PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 11, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at