rs121434369
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000159.4(GCDH):c.1204C>T(p.Arg402Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,613,810 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. R402Q) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
GCDH
NM_000159.4 missense
NM_000159.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 2.87
Genes affected
GCDH (HGNC:4189): (glutaryl-CoA dehydrogenase) The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family. It catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. The enzyme exists in the mitochondrial matrix as a homotetramer of 45-kD subunits. Mutations in this gene result in the metabolic disorder glutaric aciduria type 1, which is also known as glutaric acidemia type I. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 12. [provided by RefSeq, Mar 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
In a helix (size 10) in uniprot entity GCDH_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) in NM_000159.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-12897825-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973
PP5
Variant 19-12897824-C-T is Pathogenic according to our data. Variant chr19-12897824-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12897824-C-T is described in Lovd as [Pathogenic]. Variant chr19-12897824-C-T is described in Lovd as [Pathogenic]. Variant chr19-12897824-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GCDH | NM_000159.4 | c.1204C>T | p.Arg402Trp | missense_variant | Exon 11 of 12 | ENST00000222214.10 | NP_000150.1 | |
| GCDH | NM_013976.5 | c.1204C>T | p.Arg402Trp | missense_variant | Exon 11 of 12 | NP_039663.1 | ||
| GCDH | NR_102316.1 | n.1367C>T | non_coding_transcript_exon_variant | Exon 11 of 12 | ||||
| GCDH | NR_102317.1 | n.1585C>T | non_coding_transcript_exon_variant | Exon 10 of 11 |
Ensembl
Frequencies
GnomAD3 genomes 0.000178 AC: 27AN: 152018Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000322 AC: 81AN: 251294Hom.: 0 AF XY: 0.000346 AC XY: 47AN XY: 135860
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GnomAD4 exome AF: 0.000238 AC: 348AN: 1461792Hom.: 0 Cov.: 32 AF XY: 0.000235 AC XY: 171AN XY: 727216
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GnomAD4 genome 0.000178 AC: 27AN: 152018Hom.: 0 Cov.: 31 AF XY: 0.000162 AC XY: 12AN XY: 74236
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:21Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:14Other:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Jan 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The GCDH c.1204C>T (p.Arg402Trp) variant has been described in at least nine studies and is found in at least 63 individuals with glutaric acidemia, including 26 in a homozygous state, 18 in a compound heterozygous state, and nine in a heterozygous state (Biery et al. 1996; Schwartz et al. 1998; Busquets et al. 2000a; Busquets et al. 2000b; Busquets et al. 2000c; Zschocke et al. 2000; Fraidakis et al. 2014; Georgiou et al. 2014; Gupta et al. 2015). The variant is found in an additional 24 disease alleles of unknown zygosity (Biery et al. 1996; Zschocke et al. 2000). The p.Arg402Trp variant has been described as the most common variant in different populations being present in 10-20% of alleles in affected individuals (Zschocke et al. 2000; Fraidakis et al. 2014). The p.Arg402Trp variant was absent from 100 unrelated Spanish controls and is reported at a frequency of 0.00076 in the European (Finnish) population of the Exome Aggregation Consortium. Expression of the p.Arg402Trp variant in E.coli and cultured fibroblasts showed reduced GCD activity compared to wild type, with 3% and <1% residual activity, respectively (Biery et al. 1996; Busquets et al. 2000b; Schwartz et al. 1998). Keyser et al. (2008) also demonstrated a reduced enzyme activity for the variant of 1.6% of wild type in mammalian cells and an increased degradation of the protein compared to wild type. The Arg402 residue is highly conserved. Based on the collective evidence, the p.Arg402Trp variant is classified as pathogenic for glutaric acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 06, 2017 | Variant summary: The GCDH c.1204C>T (p.Arg402Trp) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 27/120918 control chromosomes at a frequency of 0.0002233, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). The variant was found in multiple affected individuals with an established diagnosis of GA-I based on the clinical symptoms, characteristic findings on neuroimaging and quantitative analysis of organic acids in urine. Busquets (2000) and Zschocke (2000) report the frequency of the variant of interest in affected individuals as 22% and 25%, respectively. Functional studies using expression systems show the variant to have a complete loss of GCDH activity (Biery_1996, Keyser_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2000 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Feb 02, 2018 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | Most common pan ethnic pathogenic variant - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 27, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jun 01, 2020 | PS3, PS4_Supporting, PM2, PM3_Strong, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Nov 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 06, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 04, 2019 | NM_000159.2(GCDH):c.1204C>T(R402W) is classified as likely pathogenic in the context of GCDH-related glutaric acidemia. Sources cited for classification include the following: PMID 8900227, 10699052, 24973495 and 18775954. Classification of NM_000159.2(GCDH):c.1204C>T(R402W) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 15, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 402 of the GCDH protein (p.Arg402Trp). This variant is present in population databases (rs121434369, gnomAD 0.07%). This missense change has been observed in individual(s) with glutaric acidemia I and is the most common cause of glutaric acidemia I in Europe (PMID: 8900227, 10649503, 11073722, 20732827, 28352331, 28438223). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2085). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GCDH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCDH function (PMID: 8900227, 18775954). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 15, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 08, 2020 | Functional studies in E.coli and BHK cells transfected with R402W mutant plamids demonstrated reduced GCDH enzyme expression as compared to wild type, and upon cross-linkage, the formation of homotetrameric GCDH was strongly impaired in the R402W mutants (Biery et al., 1996; Keyser et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9711871, 32056211, 10699052, 25087612, 8900227, 18775954, 10960496, 24973495, 25762492, 28438223, 28352331, 29292490, 30217722, 30570710, 31062211, 25256449, 10649503, 20732827, 31589614, 32777384, 32240488) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 20, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | GCDH: PM3:Very Strong, PS3, PM1, PM2, PM5, PP3 - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 14, 2021 | The c.1204C>T (p.R402W) alteration is located in exon 11 (coding exon 10) of the GCDH gene. This alteration results from a C to T substitution at nucleotide position 1204, causing the arginine (R) at amino acid position 402 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.03% (89/282634) total alleles studied. The highest observed frequency was 0.08% (19/25112) of European (Finnish) alleles. This mutation has been reported in the homozygous and compound heterozygous state in multiple individuals with GCDH-related glutaricadicuria (Biery, 1996; Busquets, 2000; Zayed, 2019; Pokora, 2019). In E. coli and BHK cells, GCDH activity was reduced compared to wild type (Biery, 1996; Keyser, 2008). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Primary ciliary dyskinesia 29 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | The missense c.1204C>T(p.Arg402Trp) variant in GCDH gene has been reported previously in homozygous and compound heterozygous state in individuals affected with type I glutaric aciduria (Boy et al. 2017; Zayed et al. 2019). The variant is the most common missense change in individuals affected with type I glutaric aciduria (Zayed et al. 2019). Experimental studies show that this variant leads to rapid intramitochondrial degradation causing a significantly reduced protein compared with cells expressing wild-type protein (Keyser et al. 2008). The p.Arg402Trp variant is reported with an allele frequency of 0.03% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg402Trp in GCDH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 402 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
Abnormality of metabolism/homeostasis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at