rs1555749239

chr19-12891895-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1 PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000159.4(GCDH):c.192G>T(p.Glu64Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.30

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.

• PS1: Transcript NM_000159.4 (GCDH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000159.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant 19-12891895-G-T is Pathogenic according to our data. Variant chr19-12891895-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12891895-G-T is described in Lovd as [Pathogenic]. Variant chr19-12891895-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.192G>T	p.Glu64Asp	missense_variant	4/12	ENST00000222214.10
GCDH	NM_013976.5	c.192G>T	p.Glu64Asp	missense_variant	4/12
GCDH	NR_102316.1	n.300G>T		non_coding_transcript_exon_variant	4/12
GCDH	NR_102317.1	n.608G>T		non_coding_transcript_exon_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.192G>T	p.Glu64Asp	missense_variant	4/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 07, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 64 of the GCDH protein (p.Glu64Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 24973495). ClinVar contains an entry for this variant (Variation ID: 550794). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Biochemical Genetics Department, Cyprus Institute of Neurology and Genetics	-	In silico analysis of the p.Glu64Asp variant predicted it as deleterious. Seven different bioinformatic tools (PolyPhen-2, SIFT, PANTHER, Condel, Eris, Mupro and PhD-SNP) were used for this prediction. The p.Glu64Asp variant has been also reported in a family of Arab-Muslim first-degree consanguineous parents with their second found to be affected (Pode-Shakked et., 2014). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;D;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.0	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D;.;.;.;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.;.;.;.
Sift4G	Uncertain	0.047	D;D;D;D;D
Polyphen		0.86	P;.;P;.;.
Vest4		0.73
MutPred		0.60		Loss of disorder (P = 0.2509);Loss of disorder (P = 0.2509);Loss of disorder (P = 0.2509);.;Loss of disorder (P = 0.2509);
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.92
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555749239; hg19: chr19-13002709;