rs121434371

chr19-12896934-G-Achr19-12896934-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000159.4(GCDH):c.877G>A(p.Ala293Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,613,110 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A293V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:2
• Conservation: PhyloP100: 9.70

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain 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 chr19-12896935-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2864675.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 19-12896934-G-A is Pathogenic according to our data. Variant chr19-12896934-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12896934-G-A is described in Lovd as [Pathogenic]. Variant chr19-12896934-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.877G>A	p.Ala293Thr	missense_variant	9/12	ENST00000222214.10
GCDH	NM_013976.5	c.877G>A	p.Ala293Thr	missense_variant	9/12
GCDH	NR_102316.1	n.1040G>A		non_coding_transcript_exon_variant	9/12
GCDH	NR_102317.1	n.1258G>A		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.877G>A	p.Ala293Thr	missense_variant	9/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000599 AC: 15 AN: 250466 Hom.: 0 AF XY: 0.0000738 AC XY: 10 AN XY: 135568

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1460874 Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38 AN XY: 726794

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74372

Gnomad4 AFR AF: 0.000289

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000511 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:16 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2017	Variant summary: The GCDH c.877G>A (p.Ala293Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC and cohorts reported in the literature at a frequency of 0.0002717 (33/121474 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). In the literature, the variant has been identified in numerous patients with glutaric acidemia type 1 in a homozygous and compound heterozygous state (van der Watt_MGM_2010; Christensen_JIMD_2004). Each of these studies also performed GCDH enzyme activity assays, which showed that the variant is a functional null allele, resulting in undetectable or very low activity (van der Watt_MGM_2010; Christensen_JIMD_2004). In addition, 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, no assertion criteria provided	literature only	OMIM	Nov 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 08, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 supporting, PM3 strong, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2022	The p.Ala293Thr variant in GCDH has been reported in at least 20 individuals with glutaric aciduria type 1, including eleven compound heterozygotes and five homozygotes, and segregated with disease in three affected individuals from three families (Biery 1996 PMID: 8900227, Ojwang 2001 PMID: 12199454, Mahfoud 2004 PMID: 15573311, Adhikari 2020 PMID: 32778825, Sitta 2021 PMID: 33064266, Busquets 2000 PMID: 10960496). It has also been identified in is 0.0290% (12/41462) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 2083). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function by eliminating glutaryl-CoA dehydrogenase activity (Busquets 2000 PMID:10960496); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glutaryl-CoA dehydrogenase deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PP4, PP1_Strong, PS3_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 293 of the GCDH protein (p.Ala293Thr). This variant is present in population databases (rs121434371, gnomAD 0.04%). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 8900227, 8900228, 10960496, 12199454, 15573311). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2083). 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 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). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	-	PS3+PS4+PM3+PP3+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 23, 2018	Across a selection of the available literature, the GCDH c.877G>A (p.Ala293Thr) variant has been identified in a homozygous state in 21 probands with glutaric acidemia and one asymptomatic individual, in a compound heterozygous state in 15 affected probands, and in a heterozygous state in 23 healthy individuals (Biery et al. 1996; Anikster et al. 1996; Busquets et al. 2000; Christensen et al. 2004; Van der Watt et al. 2010; Flamand-Rouviere et al. 2010). The p.Ala293Thr variant was absent from 50 controls but is reported at a frequency of 0.00058 in the African population of the Exome Aggregation Consortium. Functional studies performed in vivo using proband fibroblast or leukocyte cells demonstrated that the p.Ala293Thr variant resulted in zero to eleven percent of normal glutaryl-CoA dehydrogenase enzyme activity compared to controls, with homozygotes exhibiting less than one percent activity (Busquets et al. 2000; Christensen et al. 2004; Kolker et al. 2006; Flamand-Rouviere et al. 2010). Based on the collective evidence, the p.Ala293Thr 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 07, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	Founder variant in South African Xhosa peoples -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant classified as Pathogenic and reported on 05-09-2022 by Invitae . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2022	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: 17188916, 8900228, 8900227, 31536184, 9711871, 28794906, 27397597, 28281424, 25087612, 20629163, 15505393, 15573311, 12199454, 32556492, 20732827, 19433437, 16641220, 10960496, 28062662, 29086383, 30570710, 26071121, 33064266, 32778825) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MVP		1.0
MPC		1.1
ClinPred		0.67	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.86

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

Other links and lift over

dbSNP: rs121434371; hg19: chr19-13007748;