14-54902545-G-C

Variant names:

• chr14-54902545-G-C
• rs995999325
• NM_000161.3:c.119C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000161.3(GCH1):​c.119C>G​(p.Pro40Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000862 in 1,392,624 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P40P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: GCH1 NM_000161.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0610
• 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: Likely_benign. The variant received -1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21263087).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000161.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	NM_000161.3	MANE Select	c.119C>G	p.Pro40Arg	missense	Exon 1 of 6	NP_000152.1
	GCH1	NM_001024024.2		c.119C>G	p.Pro40Arg	missense	Exon 1 of 7	NP_001019195.1
	GCH1	NM_001024070.2		c.119C>G	p.Pro40Arg	missense	Exon 1 of 7	NP_001019241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	ENST00000491895.7	TSL:1 MANE Select	c.119C>G	p.Pro40Arg	missense	Exon 1 of 6	ENSP00000419045.2
	GCH1	ENST00000395514.5	TSL:1	c.119C>G	p.Pro40Arg	missense	Exon 1 of 7	ENSP00000378890.1
	GCH1	ENST00000543643.6	TSL:1	c.119C>G	p.Pro40Arg	missense	Exon 1 of 7	ENSP00000444011.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000712 AC: 1 AN: 140534 AF XY: 0.0000130

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: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000862 AC: 12 AN: 1392624 Hom.: 0 Cov.: 32 AF XY: 0.00000727 AC XY: 5 AN XY: 687688

African (AFR) AF: 0.00 AC: 0 AN: 29512

American (AMR) AF: 0.00 AC: 0 AN: 35338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24416

East Asian (EAS) AF: 0.00 AC: 0 AN: 34752

South Asian (SAS) AF: 0.00 AC: 0 AN: 78530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4684

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1079286

Other (OTH) AF: 0.00 AC: 0 AN: 57556

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with arginine at codon 40 of the GCH1 protein (p.Pro40Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. 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. This variant has not been reported in the literature in individuals affected with GCH1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.

Inborn genetic diseases Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119C>G (p.P40R) alteration is located in exon 1 (coding exon 1) of the GCH1 gene. This alteration results from a C to G substitution at nucleotide position 119, causing the proline (P) at amino acid position 40 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.21	T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	-0.90	N
PhyloP100		0.061
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.050	N
REVEL	Uncertain	0.36
Sift	Benign	0.21	T
Sift4G	Benign	0.28	T
Polyphen		0.0050	B
Vest4		0.14
MutPred		0.27		Gain of MoRF binding (P = 0.0106)
MVP		0.63
MPC		1.1
ClinPred		0.040	T
GERP RS		-0.18
PromoterAI		0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.044
gMVP		0.50
Mutation Taster		=93/7	polymorphism

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: rs995999325; hg19: chr14-55369263;