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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 2.87

Variant links:

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]

GCDH links:

Genome browser will be placed here

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
GCDH	NM_000159.4 link	c.1204C>T	p.Arg402Trp	missense_variant	Exon 11 of 12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5 link	c.1204C>T	p.Arg402Trp	missense_variant	Exon 11 of 12		NP_039663.1
GCDH	NR_102316.1 link	n.1367C>T		non_coding_transcript_exon_variant	Exon 11 of 12
GCDH	NR_102317.1 link	n.1585C>T		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10 link	c.1204C>T	p.Arg402Trp	missense_variant	Exon 11 of 12	1	NM_000159.4	ENSP00000222214.4		Q92947-1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000322

AC:

AN:

251294

Hom.:

AF XY:

0.000346

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000238

AC:

348

AN:

1461792

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

171

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.000768

Gnomad4 NFE exome

AF:

0.000228

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000178

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000525

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000290

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

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

Dec 04, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 06, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2019

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Most common pan ethnic pathogenic variant -

Feb 02, 2018

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_Supporting, PM2, PM3_Strong, PP4 -

not provided

Pathogenic:4

Feb 15, 2018

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GCDH: PM3:Very Strong, PS3, PM1, PM2, PM5, PP3 -

Jul 08, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Inborn genetic diseases

Pathogenic:1

Aug 14, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 01, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

5.1

H;H

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-7.5

D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.95

MVP

1.0

MPC

1.2

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over