rs149120354

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000159.4(GCDH):c.572T>C(p.Met191Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,613,886 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

GCDH
NM_000159.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.62

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.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 19-12896058-T-C is Pathogenic according to our data. Variant chr19-12896058-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12896058-T-C is described in Lovd as [Pathogenic]. Variant chr19-12896058-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GCDH	NM_000159.4 link	c.572T>C	p.Met191Thr	missense_variant	Exon 7 of 12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5 link	c.572T>C	p.Met191Thr	missense_variant	Exon 7 of 12		NP_039663.1
GCDH	NR_102316.1 link	n.735T>C		non_coding_transcript_exon_variant	Exon 7 of 12
GCDH	NR_102317.1 link	n.988T>C		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10 link	c.572T>C	p.Met191Thr	missense_variant	Exon 7 of 12	1	NM_000159.4	ENSP00000222214.4		Q92947-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251460

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135916

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:

0.0000924

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000291

AC:

425

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000308

AC XY:

224

AN XY:

727226

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:

0.0000562

Gnomad4 NFE exome

AF:

0.000366

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000151

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00171

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glutaric aciduria, type 1

Pathogenic:7

Mar 16, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 15, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2018

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.572T>C (p.Met191Thr) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase central domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-05 in 277158 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1, allowing no conclusion about variant significance. The c.572T>C has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1. 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. The most pronounced variant effect results in <10% of normal activity. Three 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 191 of the GCDH protein (p.Met191Thr). This variant is present in population databases (rs149120354, gnomAD 0.02%). This missense change has been observed in individual(s) with GCDH enzymatic activity <0.5% of wild-type, findings that are highly specific for glutaric aciduria type I (PMID: 9600243). ClinVar contains an entry for this variant (Variation ID: 198396). 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%. For these reasons, this variant has been classified as Pathogenic. -

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Apr 20, 2015

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

1.9

L;L

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.8

D;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.94

P;P

Vest4

0.94

MVP

1.0

MPC

1.2

ClinPred

0.67

GERP RS

4.9

Varity_R

0.97

gMVP

0.90

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