rs104894435

Positions:

• chr14-54902341-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000161.3(GCH1):​c.323G>A​(p.Gly108Asp) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCH1 NM_000161.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.47

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain GTP cyclohydrolase 1 (size 249) in uniprot entity GCH1_HUMAN there are 25 pathogenic changes around while only 3 benign (89%) in NM_000161.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 14-54902341-C-T is Pathogenic according to our data. Variant chr14-54902341-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9282.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCH1	NM_000161.3	c.323G>A	p.Gly108Asp	missense_variant	1/6	ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7	c.323G>A	p.Gly108Asp	missense_variant	1/6	1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families. The GCH1 gene is reported to exhibit gender-related incomplete penetrance of disease. Consistent with this variability, this variant has been reported in individuals with clinical presentations ranging from severe DRD, to adult-onset parkinsonism, to asymptomatic. Computational tools predict that this variant is damaging. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2023	Identified with a second variant in this gene in a patient with motor delay, dysarthria, and dystonia (PMID: 9667588); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18044725, 19332422, 10984668, 9667588) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 02, 2023	PP1, PP3, PP4, PM2_moderate, PM5, PS4 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 108 of the GCH1 protein (p.Gly108Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dystonia (PMID: 9667588, 15753436; Invitae). ClinVar contains an entry for this variant (Variation ID: 9282). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCH1 protein function with a positive predictive value of 80%. This variant disrupts the p.Gly108 amino acid residue in GCH1. Other variant(s) that disrupt this residue have been observed in individuals with GCH1-related conditions (PMID: 16917893, 17898029), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	.;D;D;.;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.3	M;M;M;M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.7	.;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.90
MutPred		0.96		Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.98
gMVP		0.99

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: rs104894435; hg19: chr14-55369059;