rs1393095176

chr14-54902321-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000161.3(GCH1):c.343G>A(p.Asp115Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCH1 NM_000161.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.75

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain GTP cyclohydrolase 1 (size 249) in uniprot entity GCH1_HUMAN there are 70 pathogenic changes around while only 7 benign (91%) in NM_000161.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 14-54902321-C-T is Pathogenic according to our data. Variant chr14-54902321-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449486.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCH1	NM_000161.3	c.343G>A	p.Asp115Asn	missense_variant, splice_region_variant	1/6	ENST00000491895.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCH1	ENST00000491895.7	c.343G>A	p.Asp115Asn	missense_variant, splice_region_variant	1/6	1	NM_000161.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2017

The D115N (c.343 G>A) variant in the GCH1 gene has previously been reported in an individual with childhood onset primary torsion dystonia which was responsive to benzhexol therapy (Jarman et al., 1997). This variant was also detected in this individual's unaffected father and brother (Jarman et al., 1997). The D115N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D115N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, several in-silico splice prediction models predict that c.343 G>A variant responsible for D115N damages the natural donor site of intron 1 and may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;.;D;.
Eigen	Benign	-0.071
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Uncertain	2.4	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
Sift4G	Uncertain	0.032	D;D;D;D;D
Polyphen		0.014	B;B;B;B;B
Vest4		0.76
MutPred		0.73		Loss of phosphorylation at T112 (P = 0.1323);Loss of phosphorylation at T112 (P = 0.1323);Loss of phosphorylation at T112 (P = 0.1323);Loss of phosphorylation at T112 (P = 0.1323);Loss of phosphorylation at T112 (P = 0.1323);
MVP		0.96
MPC		1.0
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.69
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.10		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: rs1393095176; hg19: chr14-55369039;