14-54847098-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000161.3(GCH1):​c.541+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GCH1
NM_000161.3 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.06
Variant links:
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
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-54847098-C-G is Pathogenic according to our data. Variant chr14-54847098-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 465762.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GCH1NM_000161.3 linkc.541+1G>C splice_donor_variant, intron_variant Intron 4 of 5 ENST00000491895.7 NP_000152.1 P30793-1A0A024R642

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GCH1ENST00000491895.7 linkc.541+1G>C splice_donor_variant, intron_variant Intron 4 of 5 1 NM_000161.3 ENSP00000419045.2 P30793-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
11
GnomAD4 genome
Cov.:
32

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
Jun 25, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 of the GCH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in several individuals affected with dopa-responsive dystonia (PMID: 11113234, 15753436, Invitae). ClinVar contains an entry for this variant (Variation ID: 465762). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
32
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
1.0
D
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.99
Position offset: 1

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.

Other links and lift over

dbSNP: rs1555358599; hg19: chr14-55313816; API