ClinVar Miner

Submissions for variant NM_000360.4(TH):c.850G>A (p.Gly284Ser)

gnomAD frequency: 0.00001  dbSNP: rs1288483479
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674870 SCV000800274 likely pathogenic Autosomal recessive DOPA responsive dystonia 2018-05-29 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000674870 SCV002016888 likely pathogenic Autosomal recessive DOPA responsive dystonia 2020-05-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000674870 SCV002228453 pathogenic Autosomal recessive DOPA responsive dystonia 2024-03-17 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 315 of the TH protein (p.Gly315Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of tyrosine hydroxylase deficiency (PMID: 22264700, 25758715, 28087438, 32005694). 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: 558576). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000674870 SCV004029969 pathogenic Autosomal recessive DOPA responsive dystonia 2023-07-24 criteria provided, single submitter clinical testing Variant summary: TH c.943G>A (p.Gly315Ser) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of 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 7e-06 in 143142 control chromosomes (gnomAD). c.943G>A has been reported in the literature in multiple individuals with clinical features of tyrosine hydroxylase deficiency (example: Mak_2010, Chi_2012, Mercimek-Mahmutoglu_2015, Cordeiro_2018, and Dong_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22264700, 30109838, 32005694, 20056467, 25758715). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000674870 SCV005054275 pathogenic Autosomal recessive DOPA responsive dystonia 2024-03-28 criteria provided, single submitter clinical testing

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