rs121434372

Positions:

chr19-12897818-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000159.4(GCDH):c.1198G>A(p.Val400Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,614,012 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 (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

GCDH
NM_000159.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 3.46

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 14 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

PP5

Variant 19-12897818-G-A is Pathogenic according to our data. Variant chr19-12897818-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12897818-G-A is described in Lovd as [Pathogenic]. Variant chr19-12897818-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GCDH	NM_000159.4 link	c.1198G>A	p.Val400Met	missense_variant	11/12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5 link	c.1198G>A	p.Val400Met	missense_variant	11/12		NP_039663.1
GCDH	NR_102316.1 link	n.1361G>A		non_coding_transcript_exon_variant	11/12
GCDH	NR_102317.1 link	n.1579G>A		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10 link	c.1198G>A	p.Val400Met	missense_variant	11/12	1	NM_000159.4	ENSP00000222214.4		Q92947-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251356

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000125

AC:

183

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000150

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000151

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000147

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glutaric aciduria, type 1

Pathogenic:10Other:1

not provided, no classification provided	literature only	GeneReviews	-	common variant among low excreters in Spain -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 15, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 400 of the GCDH protein (p.Val400Met). This variant is present in population databases (rs121434372, gnomAD 0.02%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 10960496, 21912879, 27397597). ClinVar contains an entry for this variant (Variation ID: 2088). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2017	Variant summary: The GCDH c.1198G>A (p.Val400Met) variant involves the alteration of a conserved nucleotide that lies within the acyl-CoA dehydrogenase/oxidase C-terminal domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 28/277188 control chromosomes at a frequency of 0.000101, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). The variant has been identified in numerous glutaric acidemia I patients in homozygosity and compound heterozygosity (Busquets_2000; Christensen_2004). Studies on the residual GCDH enzyme activity levels in these patients show a range from almost no activity when in compound heterozygosity with a known null mutation (e.g., R402W), up to 30% of normal activity when in compound heterozygosity with a mild mutation (e.g., R227P). In homozygosity, the GCDH activity levels were 5-15% of WT ( Busquets_2000 and CHRISTENSEN_2004). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 17, 2023	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8900227, 26847429, 26071121, 9881681, 9711871, 31536184, 15505393, 21912879, 27397597, 10960496, 31491587, 31589614, 32240488, 32778825, 32992790) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 05, 2017	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2022

The c.1198G>A (p.V400M) alteration is located in exon 11 (coding exon 10) of the GCDH gene. This alteration results from a G to A substitution at nucleotide position 1198, causing the valine (V) at amino acid position 400 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of 0.011% (30/282716) total alleles studied. The highest observed frequency was 0.028% (2/7222) of Other alleles. This variant has been observed in the homozygous state and confirmed in trans with GCDH pathogenic variants in multiple individuals with clinical features of GCDH-related glutaricaciduria (Cerisola, 2009; Busquets, 2000; Marti-Masso, 2012; Biery, 1996; Del Rizzo, 2016; Schillaci, 2016; Kurkina, 2020; Martin-Rivada, 2022). This amino acid position is highly conserved in available vertebrate species. Functional studies show reduced enzyme activity in patient-derived fibroblasts or leukocytes (Christensen, 2004). Additionally, functional studies show reduced stability and ligand binding compared to controls in vitro (Ribeiro, 2020a; Ribeiro, 2020b). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

GCDH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2024

The GCDH c.1198G>A variant is predicted to result in the amino acid substitution p.Val400Met. This variant has previously been reported as a common variant causative for glutaric acidemia type I (for example, Biery et al. 1996. PubMedID: 8900227; Busquets et al. 2000. PubMed ID: 10960496; Christensen et al. 2004. PubMed ID: 15505393). The p.Val400Met has been reported to reduce enzyme activity to ~5-15% of wild-type (Busquets et al. 2000. PubMed ID: 10960496; Christensen et al. 2004. PubMed ID: 15505393). This variant is reported in 0.016% of alleles in individuals of European (non-Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;M

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.5

N;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.038

D;D

Polyphen

1.0

D;D

Vest4

0.80

MVP

0.99

MPC

0.82

ClinPred

0.54

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.95

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