ClinVar Miner

Submissions for variant NM_000360.4(TH):c.628G>A (p.Ala210Thr)

dbSNP: rs1260455415
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668727 SCV000793374 uncertain significance Autosomal recessive DOPA responsive dystonia 2017-08-15 criteria provided, single submitter clinical testing
Mendelics RCV000668727 SCV002519868 pathogenic Autosomal recessive DOPA responsive dystonia 2022-05-04 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000668727 SCV004048394 likely pathogenic Autosomal recessive DOPA responsive dystonia criteria provided, single submitter clinical testing The missense variant c.721G>A (p.Ala241Thr) in TH gene has been reported in affected individuals (Willemsen et al., 2010). The functional studies performed have unclear results. The observed variant gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. The p.Ala241Thr variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Ala at position 241 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ala241Thr in TH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV000668727 SCV004203877 likely pathogenic Autosomal recessive DOPA responsive dystonia 2023-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668727 SCV004803431 likely pathogenic Autosomal recessive DOPA responsive dystonia 2024-01-15 criteria provided, single submitter clinical testing Variant summary: TH c.721G>A (p.Ala241Thr) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.721G>A has been reported in the literature in individuals affected with Segawa Syndrome, Autosomal Recessive (example: Willemsen_2010). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Fossbakk_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24753243, 20430833). ClinVar contains an entry for this variant (Variation ID: 553311). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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