rs786204526

chr19-12896338-C-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.769C>T(p.Arg257Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,976 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R257Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.997

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr19-12896339-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 529442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 19-12896338-C-T is Pathogenic according to our data. Variant chr19-12896338-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12896338-C-T is described in Lovd as [Pathogenic]. Variant chr19-12896338-C-T is described in Lovd as [Likely_pathogenic]. Variant chr19-12896338-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.769C>T	p.Arg257Trp	missense_variant	8/12	ENST00000222214.10
GCDH	NM_013976.5	c.769C>T	p.Arg257Trp	missense_variant	8/12
GCDH	NR_102316.1	n.932C>T		non_coding_transcript_exon_variant	8/12
GCDH	NR_102317.1	n.1150C>T		non_coding_transcript_exon_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.769C>T	p.Arg257Trp	missense_variant	8/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152144 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251274 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135856

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461832 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152144 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74318

Gnomad4 AFR AF: 0.0000241

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: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000752 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 08, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 13, 2021	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2024	Variant summary: GCDH c.769C>T (p.Arg257Trp) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) 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 2e-05 in 251274 control chromosomes. c.769C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Glutaric Acidemia Type 1 (e.g. Gupta_2015, Bell_2011, Lin_2016, Wang_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21228398, 25762492, 30904546, 24332224). ClinVar contains an entry for this variant (Variation ID: 188872). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 08, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 257 of the GCDH protein (p.Arg257Trp). This variant is present in population databases (rs766518430, gnomAD 0.01%). This missense change has been observed in individual(s) with biochemical or enzymatic findings that are highly specific for glutaric aciduria type I (PMID: 9600243, 10699052, 15505393, 18683078, 19433437, 21176883, 21228398, 22728054, 24332224, 25762492; Invitae). ClinVar contains an entry for this variant (Variation ID: 188872). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 30, 2022	The p.Arg257Trp variant in GCDH has been reported in at least 9 individuals with glutaric acidemia type 1 and segregated with disease in at least 2 affected individuals from 2 families (Bijarnia 2008 PMID: 18683078, Harting 2009 PMID: 19433437, Mushimoto 2011 PMID: 21176883, Viau 2012 PMID: 22728054, Wang 2014 PMID: 24332224, Schwartz 1998 PMID: 9600243, Lin 2021 PMID: 34344405, Spenger 2021 PMID: 34207159, Paria 2022 PMID: 35662016). It has also been identified in 0.004% (3/68022) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Functional analyses of these individuals showed enzyme deficiency of GCDH (Schwartz 1998 PMID: 9600243, Harting 2009 PMID: 19433437, Mushimoto 2011 PMID: 21176883). This variant has also been reported in ClinVar (Variation ID 188872). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg257Gln) has been identified in individuals with glutaric acidemia and have been classified as pathogenic by other laboratories. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glutaric acidemia type 1. ACMG/AMP Criteria applied: PM3_Strong, PM5, PP1_Moderate, PM2_Supporting, PP3. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 30, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 10699052, 22728054, 9711871, 19433437, 18683078, 9600243, 21228398, 24332224, 21176883, 15505393, 25762492, 32508882, 32777384) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Uncertain	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.7	D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.92		Loss of disorder (P = 0.0304);Loss of disorder (P = 0.0304);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs766518430; hg19: chr19-13007152; COSMIC: COSV53366160; COSMIC: COSV53366160;