19-12899485-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4

The NM_000159.4(GCDH):c.1261G>A(p.Ala421Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,614,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. A421V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00055 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

GCDH
NM_000159.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:2O:1

Conservation

PhyloP100: 7.88

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:

SYCE2 (HGNC:27411): (synaptonemal complex central element protein 2) The protein encoded by this gene is part of the synaptonemal complex formed between homologous chromosomes during meiotic prophase. The encoded protein associates with SYCP1 and SYCE1 and is found only where chromosome cores are synapsed. [provided by RefSeq, Dec 2012]

SYCE2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a helix (size 12) in uniprot entity GCDH_HUMAN there are 10 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 chr19-12899486-C-T is described in Lovd as [Pathogenic].

PP5

Variant 19-12899485-G-A is Pathogenic according to our data. Variant chr19-12899485-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 285973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12899485-G-A is described in Lovd as [Pathogenic]. Variant chr19-12899485-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.06658238). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCDH	NM_000159.4 link	c.1261G>A	p.Ala421Thr	missense_variant	Exon 12 of 12	ENST00000222214.10	NP_000150.1
SYCE2	NM_001105578.2 link	c.613-100C>T		intron_variant	Intron 5 of 5	ENST00000293695.8	NP_001099048.1	Q6PIF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10 link	c.1261G>A	p.Ala421Thr	missense_variant	Exon 12 of 12	1	NM_000159.4	ENSP00000222214.4		Q92947-1
SYCE2	ENST00000293695.8 link	c.613-100C>T		intron_variant	Intron 5 of 5	1	NM_001105578.2	ENSP00000293695.6		Q6PIF2

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251284

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000800

AC:

117

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000545

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00183

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000167

Hom.:

Bravo

AF:

0.000756

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glutaric aciduria, type 1

Pathogenic:6Uncertain:1Other:1

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 421 of the GCDH protein (p.Ala421Thr). This variant is present in population databases (rs151201155, gnomAD 0.2%). This missense change has been observed in individual(s) with GCDH-related conditions (PMID: 27672653, 28302372). ClinVar contains an entry for this variant (Variation ID: 285973). 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 not expected to disrupt GCDH protein function with a negative predictive value of 80%. This variant disrupts the p.Ala421 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8900227, 15505393, 28438223). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 06-18-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Mar 27, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2018

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Feb 03, 2025

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.1261G>A (p.Ala421Thr) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251284 control chromosomes, predominantly at a frequency of 0.0025 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1 (0.0002 vs 0.0035), allowing no conclusion about variant significance. c.1261G>A has been reported in the literature in multiple compound heterozygous individuals affected with Glutaric Acidemia Type 1 (e.g. Christensen_2004, Tsai_2017, Wahab_2016, Dong_2020, Lin_2021, Guenzel_2021). 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 decreased enzymatic activity both in patient derived fibroblasts (Christensen_2004) and in bacterial expression systems (Goodman_1998, Westover_2003). A different variant affecting the same codon has been classified as pathogenic by our lab (c.1262C>T, p.Ala421Val), supporting the critical relevance of codon 421 to GCDH protein function. The following publications have been ascertained in the context of this evaluation (PMID: 15505393, 32005694, 9711871, 34258142, 34344405, 28302372, 27672653, 12948740). ClinVar contains an entry for this variant (Variation ID: 285973). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 09, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1Uncertain:1

Feb 13, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found A421T is associated with significantly reduced enzyme activity (PMID: 9711871, 12948740); Identified in individuals with glutaric aciduria type 1 in published literature, although clinical information was not provided (PMID: 9711871); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27672653, 28302372, 25087612, 23891399, 12948740, 28062662, 15505393, 32306145, 32005694, 34258142, 34344405, 37020324, 9711871) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;D

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.067

T;T

MetaSVM

Pathogenic

0.96

MutationAssessor

Benign

1.5

L;L

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.7

D;.

REVEL

Pathogenic

0.90

Sift

Benign

0.047

D;.

Sift4G

Benign

0.52

T;T

Polyphen

0.90

P;P

Vest4

0.70

MVP

0.98

MPC

0.72

ClinPred

0.073

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.71

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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