NM_000317.3:c.200C>T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000317.3(PTS):c.200C>T(p.Thr67Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000497 in 1,610,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000317.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152138Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251424Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135892
GnomAD4 exome AF: 0.0000535 AC: 78AN: 1458268Hom.: 0 Cov.: 31 AF XY: 0.0000648 AC XY: 47AN XY: 725706
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74318
ClinVar
Submissions by phenotype
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:10
A heterozygous missense variation in exon 4 of the PTS gene that results in the amino acid substitution of Methionine for Threonine at codon 67 was detected. The observed variant c.200C>T (p.Thr67Met) has not been found in 1000 genomes database and has a minor allele frequency of 0.05% and 0.0026% in the gnomAD and Topmed databases. The in silico prediction of the variant is pathogenic by FATHMM, SIFT, Revel and MutationTaster. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic. -
The PTS c.200C>T; p.Thr67Met variant has previously been reported in the homozygous and compound heterozygous state in several individuals affected with hyperphenylalaninemia (Oppliger T et. al.; Dudesek A et. al.). Experimental studies have shown that this missense change reduces PTS enzymatic activity (Oppliger T et. al.; Dudesek A et. al.). The p.Thr67Met variant is novel (not in any individuals) in 1000 Genomes and has a frequency of 0.007% in the gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Thr at position 67 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Thr67Met in PTS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 67 of the PTS protein (p.Thr67Met). This variant is present in population databases (rs370340361, gnomAD 0.02%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9222757, 11388593, 11438997, 11694255, 16850690, 22237589, 25758715). ClinVar contains an entry for this variant (Variation ID: 463151). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PTS function (PMID: 9222757, 11388593). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: PTS c.200C>T (p.Thr67Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251424 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PTS causing 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency (6.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.200C>T has been reported in the literature in multiple individuals affected with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency (ie. Oppliger_1997, Cordeiro_2018, Almannai_2019, etc). PTPS activity in homozygous patients fibroblasts was <10% that of wild-type (Oppliger_1997). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hyperphenylalaninemia, BH4-deficient, A, (MIM#261640). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (80 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated 6-pyruvoyl tetrahydropterin synthase (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories and has been reported in homozygous and compound heterozygous individuals with BH4 deficiency or hyperphenylalaninemia (PMIDs: 32651154, 32905092). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:2
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Western blot analysis of fibroblasts from a patient who was compound heterozygous for T67M and a second missense variant demonstrate no PTPS protein (Oppliger et al., 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25758715, 16917893, 22237589, 16850690, 9222757, 25087612, 11388593, 25525159, 19830588, 10585341, 20059486, 9222755, 11694255, 11438997, 25456745, 30275481, 31589614, 32905092, 30109838, 32651154, 33234470, 36004034, 33101986, 32778825, 33977029, 30926181, 34214291, 35098520, 32202960) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at