19-12897825-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000159.4(GCDH):​c.1205G>C​(p.Arg402Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R402Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

GCDH
NM_000159.4 missense

Scores

15
3
1

Clinical Significance

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

Conservation

PhyloP100: 7.75
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a helix (size 10) in uniprot entity GCDH_HUMAN there are 21 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 chr19-12897825-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 19-12897825-G-C is Pathogenic according to our data. Variant chr19-12897825-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3233788.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GCDHNM_000159.4 linkc.1205G>C p.Arg402Pro missense_variant Exon 11 of 12 ENST00000222214.10 NP_000150.1
GCDHNM_013976.5 linkc.1205G>C p.Arg402Pro missense_variant Exon 11 of 12 NP_039663.1
GCDHNR_102316.1 linkn.1368G>C non_coding_transcript_exon_variant Exon 11 of 12
GCDHNR_102317.1 linkn.1586G>C non_coding_transcript_exon_variant Exon 10 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GCDHENST00000222214.10 linkc.1205G>C p.Arg402Pro missense_variant Exon 11 of 12 1 NM_000159.4 ENSP00000222214.4 Q92947-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

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
Nov 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 402 of the GCDH protein (p.Arg402Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric aciduria (PMID: 32240488). ClinVar contains an entry for this variant (Variation ID: 3233788). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GCDH protein function with a positive predictive value of 80%. This variant disrupts the p.Arg402 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8900227, 10649503, 11073722, 20732827). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 25, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: GCDH c.1205G>C (p.Arg402Pro) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal domain (IPR009075) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251266 control chromosomes (gnomAD). c.1205G>C has been reported in the literature in an individual affected with Glutaric Acidemia Type 1 (Kurkina_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missense chages affecting this amino acid have been classified as pathogenic, suggeting this is a functionally important residue. The following publication has been ascertained in the context of this evaluation (PMID: 32240488). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Mar 25, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D;D
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
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
1.0
D
MutationAssessor
Pathogenic
5.1
H;H
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-6.6
D;.
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D;.
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.98
MutPred
0.96
Gain of catalytic residue at R402 (P = 0.1196);Gain of catalytic residue at R402 (P = 0.1196);
MVP
1.0
MPC
1.4
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
1.0
gMVP
1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13008639; API