rs776082304
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000159.4(GCDH):c.1239C>A(p.Tyr413Ter) variant causes a stop gained change involving the alteration of a non-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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y413Y) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 31)
Consequence
GCDH
NM_000159.4 stop_gained
NM_000159.4 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: -0.990
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 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-12897859-C-A is Pathogenic according to our data. Variant chr19-12897859-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12897859-C-A is described in Lovd as [Pathogenic]. Variant chr19-12897859-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.1239C>A | p.Tyr413Ter | stop_gained | 11/12 | ENST00000222214.10 | |
GCDH | NM_013976.5 | c.1239C>A | p.Tyr413Ter | stop_gained | 11/12 | ||
GCDH | NR_102316.1 | n.1402C>A | non_coding_transcript_exon_variant | 11/12 | |||
GCDH | NR_102317.1 | n.1620C>A | non_coding_transcript_exon_variant | 10/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCDH | ENST00000222214.10 | c.1239C>A | p.Tyr413Ter | stop_gained | 11/12 | 1 | NM_000159.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Nov 21, 2014 | - - |
GCDH-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 20, 2022 | The GCDH c.1239C>A variant is predicted to result in premature protein termination (p.Tyr413*). This variant was reported in a study of individuals with an individual with glutaric acidemia type 1, although no additional functional or segregation data was reported (Zschocke et al. 2000. PubMed ID: 10699052). It was also reported in the homozygous state in an individual identified based on abnormal newborn screen results suggestive of glutaric acidemia type 1 (Harting et al. 2009. PubMed ID: 19433437). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Nonsense variants in GCDH are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
D;D;D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at