rs886043840

Positions:

chr19-12893504-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000159.4(GCDH):c.356C>T(p.Ser119Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,948 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

GCDH
NM_000159.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 5.65

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 19-12893504-C-T is Pathogenic according to our data. Variant chr19-12893504-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 288248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12893504-C-T is described in Lovd as [Pathogenic]. Variant chr19-12893504-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.356C>T	p.Ser119Leu	missense_variant	6/12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5 linkuse as main transcript	c.356C>T	p.Ser119Leu	missense_variant	6/12		NP_039663.1
GCDH	NR_102316.1 linkuse as main transcript	n.519C>T		non_coding_transcript_exon_variant	6/12
GCDH	NR_102317.1 linkuse as main transcript	n.772C>T		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10 linkuse as main transcript	c.356C>T	p.Ser119Leu	missense_variant	6/12	1	NM_000159.4	ENSP00000222214	P1	Q92947-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251426

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000198

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:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

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:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

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	Illumina Laboratory Services, Illumina	Nov 28, 2018	The GCDH c.356C>T (p.Ser119Leu) variant has been reported in at least five studies and is found in a total of seven probands with glutaric acidemia including two in a homozygous state and five in a compound heterozygous state, which includes three siblings (Busquets et al. 2000; Christensen et al. 2004; Korman et al. 2007; Devi et al. 2016; Mosaeilhy et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000012 in the Total population of the Genome Aggregation Database. In vitro analysis in proband fibroblasts determined that the p.Ser119Leu variant is associated with significantly reduced GCDH activity ranging from zero to five percent of controls (Busquets et al. 2000; Christensen et al. 2004). Based on the evidence, the p.Ser119Leu 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, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 119 of the GCDH protein (p.Ser119Leu). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with glutaric acidemia and glutaric acidemia type 1 (PMID: 11015709, 15505393, 17188916, 28389991). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 288248). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2024	Variant summary: GCDH c.356C>T (p.Ser119Leu) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) 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 251426 control chromosomes (gnomAD). c.356C>T has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1 (examples: Busquets_2000, Christensen_2004, Radha Rama_2016, Moseilhy_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28389991, 26071121, 11015709, 15505393). ClinVar contains an entry for this variant (Variation ID: 288248). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 15, 2017	- -

not provided

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Eurofins Ntd Llc (ga)

May 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.;D;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

H;.;H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.1

D;.;.;.

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.84

MutPred

0.87

Loss of catalytic residue at S119 (P = 0.0137);.;Loss of catalytic residue at S119 (P = 0.0137);.;

MVP

0.99

MPC

1.0

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.93

gMVP

0.88

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

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