rs1555362845
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000161.3(GCH1):c.186_197delinsA(p.Asp63GlufsTer4) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E62E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
GCH1
NM_000161.3 frameshift
NM_000161.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.31
Genes affected
GCH1 (HGNC:4193): (GTP cyclohydrolase 1) This gene encodes a member of the GTP cyclohydrolase family. The encoded protein is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, catalyzing the conversion of GTP into 7,8-dihydroneopterin triphosphate. BH4 is an essential cofactor required by aromatic amino acid hydroxylases as well as nitric oxide synthases. Mutations in this gene are associated with malignant hyperphenylalaninemia and dopa-responsive dystonia. Several alternatively spliced transcript variants encoding different isoforms have been described; however, not all variants give rise to a functional enzyme. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-54902467-AGCTCGTTATCC-T is Pathogenic according to our data. Variant chr14-54902467-AGCTCGTTATCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 529414.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCH1 | NM_000161.3 | c.186_197delinsA | p.Asp63GlufsTer4 | frameshift_variant | 1/6 | ENST00000491895.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCH1 | ENST00000491895.7 | c.186_197delinsA | p.Asp63GlufsTer4 | frameshift_variant | 1/6 | 1 | NM_000161.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
GTP cyclohydrolase I deficiency;C1851920:Dystonia 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 16, 2017 | This variant has not been reported in the literature in individuals with GCH1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asp63Glufs*4) in the GCH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCH1 are known to be pathogenic (PMID: 19491146). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at