19-12896022-T-G

Variant names:

• chr19-12896022-T-G
• rs774526353
• NM_000159.4:c.536T>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000159.4(GCDH):​c.536T>G​(p.Leu179Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,872 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L179P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 7.62

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 11 ACMG points.

• PM1: In a binding_site (size 9) in uniprot entity GCDH_HUMAN there are 23 pathogenic changes around while only 0 benign (100%) 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 chr19-12896022-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 19-12896022-T-G is Pathogenic according to our data. Variant chr19-12896022-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556229.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2}. Variant chr19-12896022-T-G is described in Lovd as [Pathogenic]. Variant chr19-12896022-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCDH	NM_000159.4	c.536T>G	p.Leu179Arg	missense_variant	Exon 7 of 12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5	c.536T>G	p.Leu179Arg	missense_variant	Exon 7 of 12		NP_039663.1
GCDH	NR_102316.1	n.699T>G		non_coding_transcript_exon_variant	Exon 7 of 12
GCDH	NR_102317.1	n.952T>G		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.536T>G	p.Leu179Arg	missense_variant	Exon 7 of 12	1	NM_000159.4	ENSP00000222214.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251298 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135904

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: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461872 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727234

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: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.00209 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:3 Uncertain:2

Jan 12, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 19, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCDH c.536T>G (p.Leu179Arg) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, central domain (IPR006091) 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 1.6e-05 in 251298 control chromosomes (gnomAD). c.536T>G has been reported in the literature in multiple individuals (including homozygous occurrences) affected with Glutaric Acidemia Type 1 (Goodman_1998; Tamhankar_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 179 of the GCDH protein (p.Leu179Arg). This variant is present in population databases (rs774526353, gnomAD 0.01%). This missense change has been observed in individual(s) with glutaric aciduria type 1 (PMID: 34504725). ClinVar contains an entry for this variant (Variation ID: 556229). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.98		Gain of methylation at L179 (P = 0.0221);Gain of methylation at L179 (P = 0.0221);
MVP		0.99
MPC		1.4
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98

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: rs774526353; hg19: chr19-13006836;