14-54844099-T-G

Variant names:

• chr14-54844099-T-G
• rs41298442
• NM_000161.3:c.671A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_000161.3(GCH1):​c.671A>C​(p.Lys224Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,226 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K224R) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: GCH1 NM_000161.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22
• Publications: 28 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_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000161.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-54844099-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9283.
• 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=0.35571033).

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.671A>C	p.Lys224Thr	missense	Exon 6 of 6	NP_000152.1
	GCH1	NM_001024024.2		c.671A>C	p.Lys224Thr	missense	Exon 6 of 7	NP_001019195.1
	GCH1	NM_001424105.1		c.377A>C	p.Lys126Thr	missense	Exon 6 of 6	NP_001411034.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	ENST00000491895.7	TSL:1 MANE Select	c.671A>C	p.Lys224Thr	missense	Exon 6 of 6	ENSP00000419045.2
	GCH1	ENST00000395514.5	TSL:1	c.671A>C	p.Lys224Thr	missense	Exon 6 of 7	ENSP00000378890.1
	GCH1	ENST00000254299.8	TSL:1	n.819A>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74374

African (AFR) AF: 0.0000483 AC: 2 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 16, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCH1 c.671A>C (p.Lys224Thr) 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 was absent in 248968 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.671A>C in individuals affected with Dystonia 5 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	23
DANN	Benign	0.78
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.34	N
PhyloP100		4.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.47
Sift	Benign	0.70	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.37
MutPred		0.45		Loss of MoRF binding (P = 0.0417)
MVP		0.89
MPC		1.3
ClinPred		0.67	D
GERP RS		2.3
Varity_R		0.34
gMVP		0.91
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41298442; hg19: chr14-55310817;