rs786204470

chr19-12893630-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000159.4(GCDH):c.482G>A(p.Arg161Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,980 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. R161W) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 3.28

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 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 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 chr19-12893629-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 850424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 19-12893630-G-A is Pathogenic according to our data. Variant chr19-12893630-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12893630-G-A is described in Lovd as [Pathogenic]. Variant chr19-12893630-G-A is described in Lovd as [Pathogenic]. Variant chr19-12893630-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.482G>A	p.Arg161Gln	missense_variant	6/12	ENST00000222214.10
GCDH	NM_013976.5	c.482G>A	p.Arg161Gln	missense_variant	6/12
GCDH	NR_102316.1	n.645G>A		non_coding_transcript_exon_variant	6/12
GCDH	NR_102317.1	n.898G>A		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.482G>A	p.Arg161Gln	missense_variant	6/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251394 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135878

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74344

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000837 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2022	Variant summary: GCDH c.482G>A (p.Arg161Gln) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251394 control chromosomes. c.482G>A has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Glutaric Acidemia Type 1 (example, Popek_2010, Busquets_2000, Christensen_2004, Wang_2014). 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 (Schmiesing_2017). The most pronounced variant effect results in loss of normal GCDH enzyme activity. The variant was also demonstrated to affect GCDH protein stability, protein homo-oligomerization and binding to electron transfer flavoprotein subunit -beta (ETFB) and dihydrolipoamide S-succinyltransferase (DLST), thereby impairing the formation of multimeric enzyme complexes. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 05, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 11, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	-	- -
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	Natera, Inc.	Jan 05, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 06, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 04, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 161 of the GCDH protein (p.Arg161Gln). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCDH function (PMID: 28062662). 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 not expected to disrupt GCDH protein function. ClinVar contains an entry for this variant (Variation ID: 188789). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 9600243, 10960496, 20836999, 26593172, 28781846). This variant is present in population databases (rs777201305, gnomAD 0.006%). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 09, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	21
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.;D;D
Eigen	Benign	-0.00083
Eigen_PC	Benign	0.065
FATHMM_MKL	Benign	0.71	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;.;M;.
MutationTaster	Benign	0.55	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.1	N;.;.;.
REVEL	Uncertain	0.64
Sift	Benign	0.050	D;.;.;.
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.012	B;.;B;.
Vest4		0.44
MutPred		0.89		Gain of disorder (P = 0.117);.;Gain of disorder (P = 0.117);.;
MVP		0.95
MPC		0.42
ClinPred		0.17	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.61

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: rs777201305; hg19: chr19-13004444; COSMIC: COSV55820308; COSMIC: COSV55820308;