rs200891969

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PP2PP5BS1_Supporting

The NM_000161.3(GCH1):c.610G>A(p.Val204Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000202 in 1,600,850 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

GCH1
NM_000161.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:7

Conservation

PhyloP100: 7.91

Publications

9 publications found

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 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

GCH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000161.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.5191 (below the threshold of 3.09). Trascript score misZ: 0.62455 (below the threshold of 3.09). GenCC associations: The gene is linked to GTP cyclohydrolase I deficiency, dystonia 5, GTP cyclohydrolase I deficiency with hyperphenylalaninemia.

PP5

Variant 14-54845784-C-T is Pathogenic according to our data. Variant chr14-54845784-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161248.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000125 (19/152302) while in subpopulation SAS AF = 0.00124 (6/4824). AF 95% confidence interval is 0.000541. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. 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.610G>A	p.Val204Ile	missense_variant	Exon 5 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.610G>A	p.Val204Ile	missense_variant	Exon 5 of 6	1	NM_000161.3	ENSP00000419045.2		P30793-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000219

AC:

AN:

251266

AF XY:

0.000236

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000211

AC:

305

AN:

1448548

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

171

AN XY:

721634

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33232

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00112

AC:

AN:

85998

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.000181

AC:

199

AN:

1099820

Other (OTH)

AF:

0.000100

AC:

AN:

59934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000125

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000264

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Feb 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 20, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in the heterozygous state in individuals with dopa-responsive dystonia in whom no second variant was identified (PMID: 26230973, 27666935); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30911941, 25637381, 25525159, 20818608, 27666935, 19332422, 12874420, 30314816, 31213404, 24993959, 29484265, 32740907, 31996268, 35287262, 34670123, 34999542, 34674384, 26230973) -

Nov 11, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dystonia 5

Pathogenic:2Uncertain:1

Dec 18, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PM3_STR,PM1,PM2_SUP,PP3 -

Nov 22, 2022

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lifecell International Pvt. Ltd

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A Heterozygous Missense variant c.610G>A in Exon 5 of the GCH1 gene that results in the amino acid substitution p.Val204Ile was identified. The observed variant has a maximum allele frequency of 0.00022/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as (Likely Pathogenic/Uncertain Significance) Conflicting Interpretations [Variation ID: 161248]. The observed variation has been previously reported in patients affected with Early-Onset Generalized Dystonia (Zech M, et.al., 2017). For these reasons, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Apr 26, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GCH1 c.610G>A (p.Val204Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 251266 control chromosomes, predominantly at a frequency of 0.0011 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in GCH1 causing GTP Cyclohydrolase I Deficiency (0.00022 vs 0.0011), allowing no conclusion about variant significance. c.610G>A has been reported in the literature as compound heterozygote DOPA naive dystonia with normal serum prolactin levels (example, Furukawa_2003), early infantile onset autosomal recessive GTP Cyclohydrolase I Deficiency without Hyperphenylalaninemia (example, Opaladen_2011), DOPA responsive dystonia in compound heterozygosity where the other variant explained the phenotype and asymptomatic heterozygous family members (example, Menacci_2014, Giri_2019), generalized dystonia non responsive to DOPA (example, Beom Ahn_2019, Zech_2017), and at unknown zygosity with Transposition of the great arterie and Parkinson's disease (Blue_2022, Muldmaa_2021). These report(s) do not provide unequivocal conclusions about association of the variant with GTP Cyclohydrolase I Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31213404, 34670123, 12874420, 30911941, 24993959, 32740907, 20818608, 27666935). ClinVar contains an entry for this variant (Variation ID: 161248). Based on the evidence outlined above, the variant was classified as uncertain significance. -

GTP cyclohydrolase I deficiency;C1851920:Dystonia 5

Uncertain:1

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 204 of the GCH1 protein (p.Val204Ile). This variant is present in population databases (rs200891969, gnomAD 0.1%). This missense change has been observed in individual(s) with dopa-responsive dystonia and/or guanine triphosphate cyclohydrolase type I deficiency without hyperphenylalaninemia (PMID: 12874420, 19332422, 20818608, 24993959, 27666935, 30911941). ClinVar contains an entry for this variant (Variation ID: 161248). 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 not expected to disrupt GCH1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dystonia 5;CN305333:GTP cyclohydrolase I deficiency with hyperphenylalaninemia

Uncertain:1

Feb 27, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dopa-responsive dystonia

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Intellectual disability

Uncertain:1

Oct 18, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;D;.;D;.

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D;D;.;D

M_CAP

Pathogenic

0.82

MetaRNN

Uncertain

0.73

D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.4

M;M;M;M;M

PhyloP100

7.9

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.95

.;N;N;N;N

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.89

MVP

0.94

MPC

2.0

ClinPred

0.38

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.88

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over