rs121434370

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000159.4(GCDH):c.1093G>A(p.Glu365Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000396 in 1,614,150 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 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

GCDH
NM_000159.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 7.67

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 24) in uniprot entity GCDH_HUMAN there are 26 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, 0.896

PP5

Variant 19-12897713-G-A is Pathogenic according to our data. Variant chr19-12897713-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12897713-G-A is described in Lovd as [Pathogenic]. Variant chr19-12897713-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GCDH	NM_000159.4 link	c.1093G>A	p.Glu365Lys	missense_variant	Exon 11 of 12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5 link	c.1093G>A	p.Glu365Lys	missense_variant	Exon 11 of 12		NP_039663.1
GCDH	NR_102316.1 link	n.1256G>A		non_coding_transcript_exon_variant	Exon 11 of 12
GCDH	NR_102317.1 link	n.1474G>A		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.1093G>A	p.Glu365Lys	missense_variant	Exon 11 of 12	1	NM_000159.4	ENSP00000222214.4		Q92947-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251412

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000730

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glutaric aciduria, type 1

Pathogenic:10Other:1

Jun 10, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 03, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCDH c.1093G>A (p.Glu365Lys) results in a conservative amino acid change located in the C-terminal domain (IPR009075) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251412 control chromosomes (gnomAD). c.1093G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Glutaric Acidemia Type 1 (e.g. Nyhan_1999, Zschocke_2000, Kolker_2001, Monies_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated an almost complete loss (~1% of control) of enzymatic activity (e.g. Nyhan_1999, Kolker_2006). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=4) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 365 of the GCDH protein (p.Glu365Lys). This variant is present in population databases (rs121434370, gnomAD 0.01%). This missense change has been observed in individual(s) with glutaric acid acidemia (PMID: 8900227, 10066389, 10699052, 11174631, 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: 2086). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCDH protein function. For these reasons, this variant has been classified as Pathogenic. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Founder variant in Irish Traveler communities in the Republic of Ireland -

Feb 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 13, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM1_Supporting, PM2, PM3, PP3 -

not provided

Pathogenic:3

Sep 04, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PP4, PM2, PM3, PS3, PS4 -

Jul 07, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 14, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that E365K had significantly reduced enzymatic activity when compared with wild-type expressing cells (Nyhan et al., 1999); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32777384, 31980526, 31130284, 29721918, 28438223, 9711871, 10066389, 11174631, 10699052, 8900227, 25087612, 29555771, 30570710) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;D

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.016

D;D

Polyphen

0.93

P;P

Vest4

0.93

MVP

0.96

MPC

1.1

ClinPred

0.82

GERP RS

5.6

Varity_R

0.93

gMVP

0.96

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