11-2167896-A-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000360.4(TH):āc.614T>Cā(p.Leu205Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,610,598 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 Likely pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L205L) has been classified as Likely benign.
Frequency
Consequence
NM_000360.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TH | NM_000360.4 | c.614T>C | p.Leu205Pro | missense_variant | 5/13 | ENST00000352909.8 | |
TH | NM_199292.3 | c.707T>C | p.Leu236Pro | missense_variant | 6/14 | ||
TH | NM_199293.3 | c.695T>C | p.Leu232Pro | missense_variant | 6/14 | ||
TH | XM_011520335.3 | c.626T>C | p.Leu209Pro | missense_variant | 5/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TH | ENST00000352909.8 | c.614T>C | p.Leu205Pro | missense_variant | 5/13 | 1 | NM_000360.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000123 AC: 3AN: 244378Hom.: 0 AF XY: 0.0000151 AC XY: 2AN XY: 132752
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1458426Hom.: 0 Cov.: 33 AF XY: 0.00000552 AC XY: 4AN XY: 725272
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74340
ClinVar
Submissions by phenotype
Autosomal recessive DOPA responsive dystonia Pathogenic:9Other:1
not provided, no classification provided | literature only | GeneReviews | - | Founder variant in Greek population - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jul 01, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. This variant was detected in homozygous state. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory Cellgenetics, GMDL Cellgenetics | - | The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. This variant was detected in compound heterozygous state with c.605G>A (p.Arg202His). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1999 | - - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 20, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 04, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 24, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 16, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 236 of the TH protein (p.Leu236Pro). This variant is present in population databases (rs121917763, gnomAD 0.003%). This missense change has been observed in individual(s) with tyrosine hydroxylase deficiency (PMID: 2019643, 8817341, 12891655, 19282209, 20430833, 23480488, 24753243; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.614T>C (p.Leu205Pro). ClinVar contains an entry for this variant (Variation ID: 12325). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TH protein function. Experimental studies have shown that this missense change affects TH function (PMID: 8817341). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | TH: PM2, PM3, PS3:Moderate - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at