rs1555362835

Positions:

• chr14-54902385-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000161.3(GCH1):​c.278_279insA​(p.Thr94AspfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCH1 NM_000161.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.51

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]

ACMG classification

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 14-54902385-C-CT is Pathogenic according to our data. Variant chr14-54902385-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 465759.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.278_279insA	p.Thr94AspfsTer30	frameshift_variant	1/6	ENST00000491895.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCH1	ENST00000491895.7	c.278_279insA	p.Thr94AspfsTer30	frameshift_variant	1/6	1	NM_000161.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

GTP cyclohydrolase I deficiency;C1851920:Dystonia 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 05, 2022

This variant has not been reported in the literature in individuals affected with GCH1-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 465759). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr94Aspfs*30) 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: 9667588, 19332422, 19491146, 25557619). -

Dystonia 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 16, 2017

This sequence change inserts 1 nucleotide in exon 1 of the GCH1 mRNA (c.278dupA), causing a frameshift at codon 94. This creates a premature translational stop signal (p.Thr94Aspfs*30) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, 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

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

LitVar

Other links and lift over

dbSNP: rs1555362835; hg19: chr14-55369103;