14-54902663-T-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000161.3(GCH1):​c.1A>G​(p.Met1?) variant causes a start lost 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 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.96

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 11 pathogenic variants. Next in-frame start position is after 102 codons. Genomic position: 54902360. Lost 0.404 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-54902663-T-C is Pathogenic according to our data. Variant chr14-54902663-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 642685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCH1	NM_000161.3	c.1A>G	p.Met1?	start_lost	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>G	p.Met1?	start_lost	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

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 14, 2024

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. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with dopamine-responsive dystonia (PMID: 9576537, 17557242, 20437540, 21935284, 22373569; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 642685). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Mar 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the heterozygous state in a family, including two siblings with dopa-responsive dystonia, their unaffected father, and an unaffected child of one of the siblings, in the published literature (Naiya et al., 2012); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22373569) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.37	T;T;.;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.41	N
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	1.0	D
PROVEAN	Benign	-0.13	.;N;N;N;N
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D;D
Polyphen		0.0020	B;B;B;B;B
Vest4		0.89
MutPred		1.0		Loss of methylation at K3 (P = 0.1519);Loss of methylation at K3 (P = 0.1519);Loss of methylation at K3 (P = 0.1519);Loss of methylation at K3 (P = 0.1519);Loss of methylation at K3 (P = 0.1519);
MVP		0.99
ClinPred		1.0	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.73

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: rs1555362907; hg19: chr14-55369381;