ClinVar Miner

Submissions for variant NM_000360.4(TH):c.1147G>A (p.Gly383Arg)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002985658 SCV003291230 uncertain significance Autosomal recessive DOPA responsive dystonia 2022-05-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 414 of the TH protein (p.Gly414Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with dystonia (PMID: 18058633, 19491146). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TH function (PMID: 24753243). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity RCV002985658 SCV003828062 pathogenic Autosomal recessive DOPA responsive dystonia 2022-04-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV002985658 SCV004203832 likely pathogenic Autosomal recessive DOPA responsive dystonia 2024-02-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002985658 SCV005185370 likely pathogenic Autosomal recessive DOPA responsive dystonia 2024-05-08 criteria provided, single submitter clinical testing Variant summary: TH c.1240G>A (p.Gly414Arg) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249482 control chromosomes. c.1240G>A has been reported in the literature in multiple compound heterozygous individuals affected with Dopa-responsive dystonia with second variants of unknown pathogenicity (e.g. Clot_2009, Giovanniello_2007, Chen_2020). At least one publication reports experimental evidence evaluating an impact on protein function, showing <10% of normal enzyme activity in vitro (e.g. Fossbakk_2014). The following publications have been ascertained in the context of this evaluation (PMID: 32185155, 19491146, 24753243, 18058633). ClinVar contains an entry for this variant (Variation ID: 2077702). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002985658 SCV005676245 likely pathogenic Autosomal recessive DOPA responsive dystonia 2024-05-09 criteria provided, single submitter clinical testing

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