19-12896938-G-C

Variant names:

• chr19-12896938-G-C
• rs775606471
• NM_000159.4:c.881G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000159.4(GCDH):​c.881G>C​(p.Arg294Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.70
• Publications: 8 publications found

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]

GCDH Gene-Disease associations (from GenCC):

• glutaryl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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 chr19-12896937-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 860646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 19-12896938-G-C is Pathogenic according to our data. Variant chr19-12896938-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 430833.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000159.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	NM_000159.4	MANE Select	c.881G>C	p.Arg294Pro	missense	Exon 9 of 12	NP_000150.1
	GCDH	NM_013976.5		c.881G>C	p.Arg294Pro	missense	Exon 9 of 12	NP_039663.1
	GCDH	NR_102316.1		n.1044G>C		non_coding_transcript_exon	Exon 9 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	ENST00000222214.10	TSL:1 MANE Select	c.881G>C	p.Arg294Pro	missense	Exon 9 of 12	ENSP00000222214.4
	GCDH	ENST00000591470.5	TSL:1	c.881G>C	p.Arg294Pro	missense	Exon 8 of 11	ENSP00000466845.1
	GCDH	ENST00000714069.1		c.881G>C	p.Arg294Pro	missense	Exon 9 of 13	ENSP00000519360.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:2

Oct 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg294 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15505393, 29665094). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 430833). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 25762492, 29201125). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 294 of the GCDH protein (p.Arg294Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline.

Jun 07, 2017

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The observed variant is not reported in 1000 Genomes, ExAC and dbSNP databases but found to be pathogenic by in silico analysis using Mutation Taster, Polyphen2 and SIFT software.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		9.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.92		Loss of stability (P = 0.0504)
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs775606471; hg19: chr19-13007752;