rs777201305
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000159.4(GCDH):c.482G>A(p.Arg161Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,980 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. R161W) 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.482G>A | p.Arg161Gln | missense_variant | 6/12 | ENST00000222214.10 | |
GCDH | NM_013976.5 | c.482G>A | p.Arg161Gln | missense_variant | 6/12 | ||
GCDH | NR_102316.1 | n.645G>A | non_coding_transcript_exon_variant | 6/12 | |||
GCDH | NR_102317.1 | n.898G>A | non_coding_transcript_exon_variant | 5/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCDH | ENST00000222214.10 | c.482G>A | p.Arg161Gln | missense_variant | 6/12 | 1 | NM_000159.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152188Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251394Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135878
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461792Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727204
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152188Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74344
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:10
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 13, 2022 | Variant summary: GCDH c.482G>A (p.Arg161Gln) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251394 control chromosomes. c.482G>A has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Glutaric Acidemia Type 1 (example, Popek_2010, Busquets_2000, Christensen_2004, Wang_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Schmiesing_2017). The most pronounced variant effect results in loss of normal GCDH enzyme activity. The variant was also demonstrated to affect GCDH protein stability, protein homo-oligomerization and binding to electron transfer flavoprotein subunit -beta (ETFB) and dihydrolipoamide S-succinyltransferase (DLST), thereby impairing the formation of multimeric enzyme complexes. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 11, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 18, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 06, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 10, 2020 | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 161 of the GCDH protein (p.Arg161Gln). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCDH function (PMID: 28062662). 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 not expected to disrupt GCDH protein function. ClinVar contains an entry for this variant (Variation ID: 188789). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 9600243, 10960496, 20836999, 26593172, 28781846). This variant is present in population databases (rs777201305, gnomAD 0.006%). - |
Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 09, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at