rs566417795

chr19-12892125-G-Achr19-12892125-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_000159.4(GCDH):c.281G>A(p.Arg94Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000601 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R94W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 4.77

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 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr19-12892125-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 529446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 19-12892125-G-A is Pathogenic according to our data. Variant chr19-12892125-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12892125-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.281G>A	p.Arg94Gln	missense_variant	5/12	ENST00000222214.10
GCDH	NM_013976.5	c.281G>A	p.Arg94Gln	missense_variant	5/12
GCDH	NR_102317.1	n.697G>A		non_coding_transcript_exon_variant	4/11
GCDH	NR_102316.1	n.379+151G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.281G>A	p.Arg94Gln	missense_variant	5/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32

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: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251464 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135912

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: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.000102 AC XY: 74 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74450

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:9 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	Aug 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Nov 28, 2019	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2023	Variant summary: GCDH c.281G>A (p.Arg94Gln) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251464 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1 (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.281G>A has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (Gupta_2015, Foran_2021, Healy_2022), including two siblings. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function indicating about 2% residual activity with glutaryl- CoA as substrate (Dwyer_2001). Another variant affecting the same amino acid (c.281G>T, p.Arg94Leu) has also been associated with GA1, suggesting an important role for this amino acid. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as pathogenic (n=3), likely pathogenic (n= 4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 94 of the GCDH protein (p.Arg94Gln). This variant is present in population databases (rs566417795, gnomAD 0.1%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 25762492; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 418224). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GCDH function (PMID: 11024031). This variant disrupts the p.Arg94 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9600243). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glutaricaciduria type I (GA-I, MIM#231670). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (31 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Acyl-CoA dehydrogenase, N-terminal domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. The alternative amino acid change to leucine, p.(Arg94Leu) has been reported as likely pathogenic (3x) in ClinVar, however, it has not been used as supporting evidence as the change to leucine has a much larger Grantham score. In addition, p.(Arg94Trp) has been reported as a VUS in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in 8 individuals, including three unrelated families with GA-I (low excreter biochemical phenotype) in both compound heterozygous and homozygous state (ClinVar, PMIDs: 25762492, 31302874, 33728242, 33138774) (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Experimental studies have shown a significantly reduced Kcat of GCDH to 2% to 3% of wild type GCDH (PMID: 11024031). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.281G>A (p.Arg94Gln) in GCDH gene has been observed in combination with another GCDH variant in individual(s) with glutaric acidemia (Gupta N et.al.,2015). This variant has been reported to affect GCDH protein function (Dwyer TM et.al.,2001). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg94Gln variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.01233% is reported in gnomAD. The amino acid Arg at position 94 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg94Gln in GCDH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 28, 2022	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2016

The R94Q (c.281 G>A) variant in the GCDH gene has previously been reported in two siblings believed to have glutaric aciduria type I (GA1) who were low glutaric acid excretors and were compound heterozygous for R94Q (c.281 G>A) and another missense variant in the GCDH gene (Gupta et al. 2015). The R94Q (c.281 G>A) variant has also been seen at GeneDx in a patient sent for analysis of the GCDH gene after abnormal newborn screening results who also harbored the R402W pathogenic variant on the opposite GCDH allele (in trans). The R94Q (c.281 G>A) variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R94Q variant is a semi-conservative amino acid substitution, which occurs at a position that is highly conserved. In silico analysis predicts that R94Q is probably damaging to the protein structure/function. Furthermore, several in-silico splice prediction models predict that the c.281 G>A nucleotide substitution, responsible for R94Q, creates a cryptic acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. In summary, we interpret R94Q (c.281 G>A) to be likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D;D;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D;.;.;.
REVEL	Pathogenic	0.84
Sift	Benign	0.040	D;.;.;.
Sift4G	Uncertain	0.049	D;D;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.59
MutPred		0.53		Gain of catalytic residue at R94 (P = 0.214);Gain of catalytic residue at R94 (P = 0.214);.;Gain of catalytic residue at R94 (P = 0.214);
MVP		0.99
MPC		1.2
ClinPred		0.78	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs566417795; hg19: chr19-13002939; COSMIC: COSV53434484; COSMIC: COSV53434484;