19-12897788-G-C

Position:

• chr19-12897788-G-C

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000159.4(GCDH):​c.1168G>C​(p.Gly390Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging 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 ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G390V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.61

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 26 ACMG points.

• PS1: Transcript NM_000159.4 (GCDH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1070251
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 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 chr19-12897789-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 19-12897788-G-C is Pathogenic according to our data. Variant chr19-12897788-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 193799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12897788-G-C is described in Lovd as [Pathogenic]. Variant chr19-12897788-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.1168G>C	p.Gly390Arg	missense_variant	11/12	ENST00000222214.10
GCDH	NM_013976.5	c.1168G>C	p.Gly390Arg	missense_variant	11/12
GCDH	NR_102316.1	n.1331G>C		non_coding_transcript_exon_variant	11/12
GCDH	NR_102317.1	n.1549G>C		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.1168G>C	p.Gly390Arg	missense_variant	11/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251448 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

Gnomad AFR exome AF: 0.0000615

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: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461764 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727194

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152096 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

Gnomad4 AFR AF: 0.0000725

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: 0.0000735

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the GCDH protein (p.Gly390Arg). This variant is present in population databases (rs372983141, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of glutaric acidemia type I (PMID: 8900228, 9711871, 15505393, 17188916; Invitae). ClinVar contains an entry for this variant (Variation ID: 193799). 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%. This variant disrupts the p.Gly390 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been observed in individuals with GCDH-related conditions (PMID: 9711871, 11073722, 27672653, 30298489), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 26, 2023	Variant summary: GCDH c.1168G>C (p.Gly390Arg) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal domain (IPR009075) 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 1.2e-05 in 251448 control chromosomes (gnomAD). c.1168G>C has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (examples: Anikster_1996, Christensen_2004, Korman_2007, Kurkina_2020). Different variants affecting this residue (ex: c.1168G>A (p.Gly390Arg), c.1169G>C (p.Gly390Ala)) have been classified pathogenic/likely pathogenic in ClinVar (CV ID 1070251, 371251). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8900228, 15505393, 17188916, 32240488). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jun 21, 2022	This variant has been reported in the literature in several individuals with glutaric aciduria type 1 (GA1) in both the homozygous and compound heterozygous states (Anikster 1996 PMID: 8900228; Christensen 2003 PMID: 15505393; Korman 2007 PMID: 17188916; Boneh 2008 PMID: 18411069; Adhikari 2020 PMID: 32778825; Kurkina 2020 PMID: 32240488). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.007% [5/68020], https://gnomad.broadinstitute.org/variant/19-12897788-G-C?dataset=gnomad_r3). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is also present in ClinVar, with several laboratories classifying it as pathogenic or likely pathogenic (Variation ID: 193799). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, this variant is located in the FAD-binding domain of the encoded protein (Busquets 2000 PMID: 11073722), and several other variants at this position have been reported in individuals with GA1 (p.Gly390Ala, p.Gly390Glu, p.Gly390Trp, p.Gly390Val), further suggesting that this amino acid residue may have functional importance. In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 25, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 14, 2019	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2022	Identified in individuals suspected of GA 1 who also harbored a second GCDH variant, but it is not known whether the variants occurred on opposite alleles (in trans) (Christensen et al., 2004; Boneh et al., 2008; Barvinska et al., 2018; Kurkina et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); 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: 9711871, 17188916, 8900228, 18411069, 32778825, 15505393, 32240488, 10960496) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	5.1	H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.5	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		1.0
MutPred		0.98		Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0

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: rs372983141; hg19: chr19-13008602;