chr14-54844099-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP5BP4BS1_Supporting

The NM_000161.3(GCH1):c.671A>G(p.Lys224Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000375 in 1,614,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

GCH1
NM_000161.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:5

Conservation

PhyloP100: 4.22

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]

GCH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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;

PP5

Variant 14-54844099-T-C is Pathogenic according to our data. Variant chr14-54844099-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9283.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=5, Pathogenic=4}. Variant chr14-54844099-T-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.064124316). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000394 (60/152344) while in subpopulation AMR AF= 0.00163 (25/15304). AF 95% confidence interval is 0.00113. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCH1	NM_000161.3 link	c.671A>G	p.Lys224Arg	missense_variant	Exon 6 of 6	ENST00000491895.7	NP_000152.1	P30793-1A0A024R642

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7 link	c.671A>G	p.Lys224Arg	missense_variant	Exon 6 of 6	1	NM_000161.3	ENSP00000419045.2		P30793-1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000386

AC:

AN:

248968

Hom.:

AF XY:

0.000386

AC XY:

AN XY:

134764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000521

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000374

AC:

546

AN:

1461784

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

273

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000435

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000394

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000400

Hom.:

Bravo

AF:

0.000351

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dystonia 5

Pathogenic:3Uncertain:1

Feb 09, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Laboratory Cellgenetics, GMDL Cellgenetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria were applied in classifying this variant: PS4, PM2, PP1, PP2, PP5. -

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1Uncertain:3

Dec 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified as a single heterozygous variant in patients with childhood or adult-onset dopa-responsive dystonia or adult-onset parkinsonism referred for genetic testing at GeneDx and in published literature, and also incidentally detected in an asymptomatic family member with low urinary neopterin levels (PMID: 23430498, 15303002, 24993959, 25497597, 12391354, 37165102, 38214203); Reported as a heterozygous variant in unrelated patients with dystonia whose asymptomatic relatives also harbored the variant (PMID: 36233161, 34890878); Observed with second GCH1 variant on the opposite allele (in trans) in a patient with gait abnormalities, wrist rigidity, dystonic posturing in the arm, curling and cramping of toes, and bradykinesia, as well as postload elevation in phenylalanine after phenylalanine loading (PMID: 35083481); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17044972, 33152132, 34497580, 20981092, 12391354, 15303002, 8852666, 25497597, 24993959, 10984668, 19332422, 18044725, 9667588, 29471552, 30894892, 30314816, 27313105, 31019283, 34426522, 35893043, 36833190, 35747429, 36628429, 34674384, 23942198, 37895316, 38214203, 37165102, 34890878, 23430498, 35083481, 36233161) -

Apr 15, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2021

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families presenting with dopa-responsive dystonia (DRD). The GCH1 gene is reported to exhibit gender-related incomplete penetrance of disease. Consistent with this variability, this variant has been reported in individuals ranging in presentation from severe DRD, to adult-onset parkinsonism, to asymptomatic. -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GTP cyclohydrolase I deficiency

Pathogenic:2

Nov 05, 2021

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCH1 c.671A>G (p.Lys224Arg) results in a conservative amino acid change located in the GTP cyclohydrolase I domain (IPR020602) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 248968 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GCH1 causing GTP Cyclohydrolase I Deficiency (0.00039 vs 0.0011), allowing no conclusion about variant significance. In a cross-sectional review, c.671A>G has been reported in the literature as a compound heterozygous genotype in individuals with autosomal recessive DOPA responsive dystonia (DRD) and in individuals with autosomal dominant features of athetoid cerebral palsy, GTP-CH deficiency, DRD, Parkinson disease (PD) (example, PMID: 19332422, 8852666, 9667588, 12391354, 18044725, 23942198, 17044972, 30314816). However, due to the presence in control cohorts, the possibility of reduced penetrance cannot be excluded. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (P/LP, n=5; VUS, n=4). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dystonia 5;CN305333:GTP cyclohydrolase I deficiency with hyperphenylalaninemia

Pathogenic:2

Nov 01, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GTP cyclohydrolase I deficiency;C1851920:Dystonia 5

Pathogenic:1

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 224 of the GCH1 protein (p.Lys224Arg). This variant is present in population databases (rs41298442, gnomAD 0.08%). This missense change has been observed in individual(s) with autosomal dominant and autosomal recessive dopa-responsive dystonia (PMID: 9667588, 12391354, 15303002, 17044972, 18044725, 19332422, 25497597, 30314816, 35083481). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This missense change has also been observed in the heterozygous state in unaffected individuals, consistent with reduced penetrance (PMID: 19332422, 23430498). ClinVar contains an entry for this variant (Variation ID: 9283). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GCH1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Dopa-responsive dystonia

Pathogenic:1

Jun 10, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.671A>G;p.(Lys224Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (PMID: 12391354; 9667588; 8852666) - PS4. The p.(Lys224Arg) was detected in trans with a Pathogenic variant (PM3: PMID: 9667588) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 12391354; 8852666) - PP1.andallele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is Likely Pathogenic -

Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive

Pathogenic:1

Oct 22, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GTP cyclohydrolase I deficiency with hyperphenylalaninemia

Pathogenic:1

Jul 26, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.037%). Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009283 /PMID: 8852666). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 9667588). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases

Uncertain:1

Nov 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.671A>G (p.K224R) alteration is located in exon 6 (coding exon 6) of the GCH1 gene. This alteration results from a A to G substitution at nucleotide position 671, causing the lysine (K) at amino acid position 224 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.0090

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;D;D

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

.;D;.

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.064

T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.94

L;L;L

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.4

.;N;N

REVEL

Uncertain

0.54

Sift

Benign

0.45

.;T;T

Sift4G

Benign

0.55

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.62

MVP

0.99

MPC

0.86

ClinPred

0.037

GERP RS

2.3

Varity_R

0.16

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over