rs752234195

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000159.4(GCDH):c.1015A>G(p.Met339Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,518 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).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GCDH
NM_000159.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.16

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000159.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 19-12897361-A-G is Pathogenic according to our data. Variant chr19-12897361-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555257.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chr19-12897361-A-G is described in Lovd as [Pathogenic]. Variant chr19-12897361-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GCDH	NM_000159.4 linkuse as main transcript	c.1015A>G	p.Met339Val	missense_variant	10/12	ENST00000222214.10
GCDH	NM_013976.5 linkuse as main transcript	c.1015A>G	p.Met339Val	missense_variant	10/12
GCDH	NR_102316.1 linkuse as main transcript	n.1178A>G		non_coding_transcript_exon_variant	10/12
GCDH	NR_102317.1 linkuse as main transcript	n.1396A>G		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10 linkuse as main transcript	c.1015A>G	p.Met339Val	missense_variant	10/12	1	NM_000159.4	P1	Q92947-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151964

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251188

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135856

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:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74220

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:

0.000189

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000514

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glutaric aciduria, type 1

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 04, 2023	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 339 of the GCDH protein (p.Met339Val). This variant is present in population databases (rs752234195, gnomAD 0.008%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 9856558, 21176883, 34504725). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 555257). 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 not expected to disrupt GCDH protein function. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 20, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

H;H

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.0

D;.

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.98

D;D

Vest4

0.88

MutPred

0.92

Loss of stability (P = 0.1157);Loss of stability (P = 0.1157);

MVP

0.99

MPC

0.64

ClinPred

0.97

GERP RS

5.5

Varity_R

0.84

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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