14-54902663-T-G

Variant names:

• chr14-54902663-T-G
• rs1555362907
• NM_000161.3:c.1A>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000161.3(GCH1):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCH1 NM_000161.3 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.96
• 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 40 pathogenic variants. Next in-frame start position is after 102 codons. Genomic position: 54902360. Lost 0.404 part of the original CDS.
• PS1: Another start lost variant in NM_000161.3 (GCH1) was described as [Pathogenic] in ClinVar as 642685
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-54902663-T-G is Pathogenic according to our data. Variant chr14-54902663-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 1452723.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.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 6	ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 6	1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1298112 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 636880

African (AFR) AF: 0.00 AC: 0 AN: 26226

American (AMR) AF: 0.00 AC: 0 AN: 24732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21520

East Asian (EAS) AF: 0.00 AC: 0 AN: 29444

South Asian (SAS) AF: 0.00 AC: 0 AN: 68258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3816

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1036962

Other (OTH) AF: 0.00 AC: 0 AN: 53730

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Sep 20, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the GCH1 mRNA. The next in-frame methionine is located at codon 102. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. Disruption of the initiator codon has been observed in individuals with autosomal dominant dopa-responsive dystonia (PMID: 9576537, 17557242, 20437540, 21935284, 22373569, 31213404). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.38	T;T;.;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.90	.;D;D;.;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
PhyloP100		2.0
PROVEAN	Benign	-0.31	.;N;N;N;N
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Benign	0.085	T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B
Vest4		0.90
MutPred		0.99		Loss of methylation at K3 (P = 0.0509);Loss of methylation at K3 (P = 0.0509);Loss of methylation at K3 (P = 0.0509);Loss of methylation at K3 (P = 0.0509);Loss of methylation at K3 (P = 0.0509);
MVP		0.98
ClinPred		1.0	D
GERP RS		3.2
PromoterAI		-0.036	Neutral
Varity_R		0.94
gMVP		0.60
Mutation Taster		=0/200	disease causing

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

Other links and lift over

dbSNP: rs1555362907; hg19: chr14-55369381;