19-12891965-C-T

Position:

chr19-12891965-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000159.4(GCDH):c.262C>T(p.Arg88Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,614,102 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R88H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

GCDH
NM_000159.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.52

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr19-12891966-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1012927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

PP5

Variant 19-12891965-C-T is Pathogenic according to our data. Variant chr19-12891965-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 189150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12891965-C-T is described in Lovd as [Pathogenic]. Variant chr19-12891965-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GCDH	NM_000159.4 linkuse as main transcript	c.262C>T	p.Arg88Cys	missense_variant	4/12	ENST00000222214.10
GCDH	NM_013976.5 linkuse as main transcript	c.262C>T	p.Arg88Cys	missense_variant	4/12
GCDH	NR_102316.1 linkuse as main transcript	n.370C>T		non_coding_transcript_exon_variant	4/12
GCDH	NR_102317.1 linkuse as main transcript	n.678C>T		non_coding_transcript_exon_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10 linkuse as main transcript	c.262C>T	p.Arg88Cys	missense_variant	4/12	1	NM_000159.4	P1	Q92947-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251424

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135900

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

727248

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000683

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glutaric aciduria, type 1

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 88 of the GCDH protein (p.Arg88Cys). This variant is present in population databases (rs142967670, gnomAD 0.01%). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 8900227, 10699052, 11073722, 19433437, 23395213, 28438223). ClinVar contains an entry for this variant (Variation ID: 189150). 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%. Experimental studies have shown that this missense change affects GCDH function (PMID: 8900227). This variant disrupts the p.Arg88 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21811973, 23395213, 24332224). 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	Baylor Genetics	Mar 19, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 14, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 16, 2018	Across a selection of the available literature, the GCDH c.262C>T (p.Arg88Cys) variant has been identified in ten probands with glutaric acidemia, including four who carried the variant in a homozygous state and six who carried the variant in a compound heterozygous state, and in an additional seven proband alleles (Biery et al. 1996; Schwartz et al. 1998; Busquets et al. 2000; Zschocke et al. 2000; Al-Dirbashi et al. 2011; Bhattacharjee et al. 2015; Schmiesing et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000108 in the European (non-Finnish) population of the Genome Aggregation Database. Expression of wild type and p.Arg88Cys variant GCDH in E. coli revealed the p.Arg88Cys variant produced stable protein, however Western blotting found no enzyme activity (Biery et al. 1996). Expression of the p.Arg88Cys variant in HeLa cells revealed expression and degradation rates similar to wild type and normal mitochondrial localization but abnormal mitochondrial architecture, while expression in HEK293T cells revealed no negative impact on oligomer formation (Schmiesing et al. 2017). Based on the collective evidence, the p.Arg88Cys variant is classified as pathogenic for glutaric acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 24, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2017	Variant summary: The GCDH c.262C>T (p.Arg88Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 6/121308 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). The variant was reported in numerous affected individuals in the literature and functional studies using both expression systems as well as patient firbroblasts show the variant to have a complete loss of GCDH activity (Biery_1996, CHRISTENSEN_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2022

Published functional studies demonstrate this variant results in glutaryl-CoA dehydrogenase activity that is less than 1% of the activity of expressed wild-type protein (Biery et al., 1996); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25255367, 24332224, 23395213, 25087612, 28438223, 28062662, 8900227, 10699052, 11073722, 19433437, 31536184, 33064266, 32778825) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.;D;D;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.84

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.6

H;.;H;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.2

D;.;.;.;.

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;.;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.85

MVP

0.99

MPC

1.3

ClinPred

1.0

GERP RS

5.3

Varity_R

0.98

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over