chr11-112233487-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PS1PM1PM2PP5BP4
The NM_000317.3(PTS):c.370G>T(p.Val124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. V124V) has been classified as Likely benign.
Frequency
Consequence
NM_000317.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTS | NM_000317.3 | c.370G>T | p.Val124Leu | missense_variant | 6/6 | ENST00000280362.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTS | ENST00000280362.8 | c.370G>T | p.Val124Leu | missense_variant | 6/6 | 1 | NM_000317.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 151886Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000718 AC: 18AN: 250678Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135716
GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461350Hom.: 0 Cov.: 31 AF XY: 0.0000481 AC XY: 35AN XY: 726938
GnomAD4 genome AF: 0.0000395 AC: 6AN: 152004Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74270
ClinVar
Submissions by phenotype
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:5Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 19, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 124 of the PTS protein (p.Val124Leu). This variant is present in population databases (rs150726932, gnomAD 0.01%). This missense change has been observed in individual(s) with PTPS deficiency (PMID: 11388593, 27243974). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 556231). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects PTS function (PMID: 11388593). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 22, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 04, 2024 | Criteria applied: PM3_STR,PM1_SUP,PM2_SUP,PP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 14, 2018 | The PTS c.370G>T (p.Val124Leu)missense variant has been reported in a single study in which it is found in a compound heterozygous state with a second missense variant in one individual with a mild presentation of 6-pyruvoyltetrahydropterin synthase deficiency (Dudesek et al. 2000). Control data are unavailable for this variant, which is reported at a frequency of 0.0001454 in the Latino population of the Genome Aggregation Database. Functional studies revealed that p.Val124Leu recombinant protein had no detectable PTPS enzyme activity in COS-1 cells. Based on the limited evidence, the p.Phe56Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for 6-pyruvoyltetrahydropterin synthase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2022 | The c.370G>T (p.V124L) alteration is located in exon 6 (coding exon 6) of the PTS gene. This alteration results from a G to T substitution at nucleotide position 370, causing the valine (V) at amino acid position 124 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.007% (20/281996) total alleles studied. The highest observed frequency was 0.014% (5/35380) of Latino alleles. This alteration has been reported with a second alteration in PTS, in two patients with a mild form of 6-pyruvoyl-tetrahydropterin synthase deficiency (PTPS) (Dudesek, 2001; Yubero, 2016; Cortès-Saladelafont, 2018). This amino acid position is not well conserved in available vertebrate species. PTPS activity in fibroblast and red blood cells of the patient with p.L26F/p.V124L were low compared to controls (Dudesek, 2001). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at