rs779315456

Positions:

chr19-12896994-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.937C>T(p.Arg313Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,172 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R313Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

GCDH
NM_000159.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 2.47

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:

GCDH (HGNC:):

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 helix (size 34) in uniprot entity GCDH_HUMAN there are 30 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 chr19-12896995-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 19-12896994-C-T is Pathogenic according to our data. Variant chr19-12896994-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 379529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12896994-C-T is described in Lovd as [Pathogenic]. Variant chr19-12896994-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GCDH	NM_000159.4 linkuse as main transcript	c.937C>T	p.Arg313Trp	missense_variant	9/12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5 linkuse as main transcript	c.937C>T	p.Arg313Trp	missense_variant	9/12		NP_039663.1
GCDH	NR_102316.1 linkuse as main transcript	n.1100C>T		non_coding_transcript_exon_variant	9/12
GCDH	NR_102317.1 linkuse as main transcript	n.1318C>T		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10 linkuse as main transcript	c.937C>T	p.Arg313Trp	missense_variant	9/12	1	NM_000159.4	ENSP00000222214.4		Q92947-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

249998

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135390

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1459964

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726360

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:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glutaric aciduria, type 1

Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 313 of the GCDH protein (p.Arg313Trp). This variant is present in population databases (rs779315456, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 15505393, 25762492, 26071121). ClinVar contains an entry for this variant (Variation ID: 379529). 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: 9711871). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The GCDH c.937C>T variant has been observed to be homozygous or in combination with another GCDH variant in several individuals affected with glutaric acidemia (Gupta et. al., 2015; Christensen et. al., 2004) This variant has been reported to affect GCDH protein function (Goodman et. al., 1998). The p.Arg313Trp variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0008% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid change p.Arg313Trp in GCDH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 313 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. The above variant has been observed in spouse (RAJA_20400112292). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 03, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 03, 2021	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 2022

The c.937C>T (p.R313W) alteration is located in exon 9 (coding exon 8) of the GCDH gene. This alteration results from a C to T substitution at nucleotide position 937, causing the arginine (R) at amino acid position 313 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (2/249998) total alleles studied. The highest observed frequency was 0.01% (2/30616) of South Asian alleles. This variant has been reported in the homozygous and compound heterozygous states in patients with clinical and biochemical features of glutaricaciduria (Christensen, 2004; Wang, 2014; Gupta, 2015; Radha Rama Devi, 2016; Pokora, 2019). In addition, another variant at this position (p.R313Q) has also been reported in affected patients (Christensen, 2004; Wang, 2014). This amino acid position is highly conserved in available vertebrate species. In vitro studies demonstrated that this variant resulted in 0.2% residual enzyme activity when expressed in E. coli (Goodman, 1998). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2015

The R313W missense variant has been reported previously in association withGA1 (Goodman et al.,1998 ). This variant is associated with 0.2% of normal glutaryl-CoAdehydrogenase activity when expressed in E. coli (Goodman et al., 1998). Therefore, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

1.0

.;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

H;H

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.8

D;.

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.018

D;D

Polyphen

1.0

D;D

Vest4

0.90

MutPred

0.84

Loss of methylation at R313 (P = 0.0242);Loss of methylation at R313 (P = 0.0242);

MVP

1.0

MPC

1.2

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.93

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