rs104894434

Positions:

chr14-54844108-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000161.3(GCH1):c.662T>C(p.Met221Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

GCH1
NM_000161.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: 9.29

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:

GCH1 (HGNC:):

GCH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCH1	NM_000161.3 linkuse as main transcript	c.662T>C	p.Met221Thr	missense_variant	6/6	ENST00000491895.7	NP_000152.1	P30793-1A0A024R642

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7 linkuse as main transcript	c.662T>C	p.Met221Thr	missense_variant	6/6	1	NM_000161.3	ENSP00000419045.2		P30793-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152172

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248966

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134762

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000270

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000445

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 19, 2024	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with autosomal recessive dopa-responsive dystonia. Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 29, 2022	- -

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

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

Intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Sep 10, 2020

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 22, 2024

Variant summary: GCH1 c.662T>C (p.Met221Thr) results in a non-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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248966 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.662T>C has been reported in the literature in an individual affected with Dystonia (Furukawa_1998). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 9667588). ClinVar contains an entry for this variant (Variation ID: 9281). Based on the evidence outlined above, the variant was classified as uncertain significance. -

GTP cyclohydrolase I deficiency;C1851920:Dystonia 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 10, 2022

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 221 of the GCH1 protein (p.Met221Thr). This variant is present in population databases (rs104894434, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of GCH1-related conditions (PMID: 9667588, 30314816). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 9281). 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Sep 23, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with dystonia, DOPA-responsive (MIM#128230) and hyperphenylalaninaemia, BH4-deficient, B (MIM#233910). Missense variants have been proven to have both a loss of function and dominant negative effect on protein function, causing both dominant and recessive forms of dystonia. Only loss of function variants have been reported for hyperphenylalaninaemia (PMID: 11026444,17111153). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM, PMID: 33713342). (I) 0112 - The dominant dystonia condition associated with this gene has incomplete penetrance (PMID: 11359069). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 33713342). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to threonine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (5 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated GTP cyclohydrolase I domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Met221Val) has been submitted to ClinVar once as a VUS. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been submitted to ClinVar once as pathogenic and twice as a VUS. This variant has also been identified once in a heterozygous individual with Parkinson's disease and classified as pathogenic (PMID: 30314816), and in a compound heterozygous state in an individual with severe dystonia and developmental delay (PMID: 9667588, 9566389). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant was observed in an individual with severe dystonia and developmental delay and her unaffected father. This individual was also compound heterozygous for another GCH1 variant which segregated with DOPA-responsive dystonia in three affected members of her family, in whom this variant was not observed. However, the compound heterozygous proband was noted to be more severely affected and with earlier onset of symptoms (PMID: 9667588, 9566389). (I) 1010 - Functional evidence for this variant is inconclusive. Patient lymphoblasts from a compound heterozygous individual had reduced neopterin levels compared to controls. However, lymphoblasts from their father who is heterozygous for just this variant did not have reduced neopterin levels, while lymphoblasts from individuals with only the other variant did have reduced neopterin levels (PMID: 9566389). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Benign

0.69

DEOGEN2

Pathogenic

0.88

D;D;D

Eigen

Benign

-0.24

Eigen_PC

Benign

0.091

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;D;.

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

-0.68

N;N;N

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-2.3

.;N;N

REVEL

Uncertain

0.62

Sift

Benign

0.82

.;T;T

Sift4G

Benign

0.82

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.94

MutPred

0.74

Gain of phosphorylation at M221 (P = 0.0357);Gain of phosphorylation at M221 (P = 0.0357);Gain of phosphorylation at M221 (P = 0.0357);

MVP

0.96

MPC

1.2

ClinPred

0.24

GERP RS

5.9

Varity_R

0.49

gMVP

0.89

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

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