rs1555358382

Variant names:

• chr14-54844115-G-A
• rs1555358382
• NM_000161.3:c.655C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000161.3(GCH1):​c.655C>T​(p.Gln219*) variant causes a stop gained 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCH1 NM_000161.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.96
• Publications: 0 publications found

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]

GCH1 Gene-Disease associations (from GenCC):

• dystonia 5

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• GTP cyclohydrolase I deficiency with hyperphenylalaninemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P
• GTP cyclohydrolase I deficiency

  Inheritance: SD, AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-54844115-G-A is Pathogenic according to our data. Variant chr14-54844115-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523338.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCH1	NM_000161.3	c.655C>T	p.Gln219*	stop_gained	Exon 6 of 6	ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7	c.655C>T	p.Gln219*	stop_gained	Exon 6 of 6	1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rigidity;C0037317:Sleep abnormality;C0151786:Muscle weakness;C0575081:Gait disturbance;C0751837:Gait ataxia;C1836150:Gait imbalance Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		10
Vest4		0.83
GERP RS		5.9
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555358382; hg19: chr14-55310833;