Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000013127 | SCV002511993 | likely pathogenic | Autosomal recessive DOPA responsive dystonia | 2022-04-14 | criteria provided, single submitter | clinical testing | Variant summary: TH c.1076G>T (p.Cys359Phe) 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 was absent in 217992 control chromosomes. c.1076G>T has been reported in the literature as a homozygous genotype in at-least one individual affected with Tyrosine Hydroxylase Deficiency and continues to be reported/cited by others (example, Brautigam_1999, Dionisi-Vici_2000, Hoffmann_2003, Dong_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Fossbakk_2014). The most pronounced variant effect results in severely reduced activity compared with wt TH ( 10%), and significantly altered affinities for both tyrosine and the cofactor BH4. Interestingly, this mutation led to a higher selectivity for L-Tyrosine. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| OMIM | RCV000013127 | SCV000033374 | pathogenic | Autosomal recessive DOPA responsive dystonia | 1999-12-01 | no assertion criteria provided | literature only |