ClinVar Miner

Submissions for variant NM_000360.4(TH):c.614T>C (p.Leu205Pro)

gnomAD frequency: 0.00001  dbSNP: rs121917763
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000013118 SCV000486045 likely pathogenic Autosomal recessive DOPA responsive dystonia 2016-11-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000013118 SCV000751681 pathogenic Autosomal recessive DOPA responsive dystonia 2024-01-02 criteria provided, single submitter clinical testing 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000013118 SCV001368839 pathogenic Autosomal recessive DOPA responsive dystonia 2019-07-01 criteria provided, single submitter clinical testing 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.
CeGaT Center for Human Genetics Tuebingen RCV002274896 SCV002563043 likely pathogenic not provided 2024-07-01 criteria provided, single submitter clinical testing TH: PM2, PM3, PS3:Moderate
Fulgent Genetics, Fulgent Genetics RCV000013118 SCV002812358 likely pathogenic Autosomal recessive DOPA responsive dystonia 2022-05-20 criteria provided, single submitter clinical testing
Laboratory Cellgenetics, GMDL Cellgenetics RCV000013118 SCV003804495 pathogenic Autosomal recessive DOPA responsive dystonia criteria provided, single submitter clinical testing 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).
Baylor Genetics RCV000013118 SCV004203840 pathogenic Autosomal recessive DOPA responsive dystonia 2023-10-16 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000013118 SCV005051982 pathogenic Autosomal recessive DOPA responsive dystonia 2024-02-01 criteria provided, single submitter curation
GeneDx RCV002274896 SCV005324861 pathogenic not provided 2024-02-15 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, such that the mutant enzyme shows reduced activity compared to wild-type (PMID: 24753243, 8817341); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8817341, 23480488, 34426522, 38084654, 24753243)
OMIM RCV000013118 SCV000033365 pathogenic Autosomal recessive DOPA responsive dystonia 1999-06-01 no assertion criteria provided literature only
GeneReviews RCV000013118 SCV000172459 not provided Autosomal recessive DOPA responsive dystonia no assertion provided literature only Founder variant in Greek population
Natera, Inc. RCV000013118 SCV002085377 pathogenic Autosomal recessive DOPA responsive dystonia 2021-02-24 no assertion criteria provided clinical testing

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