Submissions for variant NM_000360.4(TH):c.1189G>C (p.Gly397Arg)

dbSNP: rs1264884607

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003511573	SCV004309923	pathogenic	Autosomal recessive DOPA responsive dystonia	2023-07-19	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 428 of the TH protein (p.Gly428Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tyrosine hydroxylase deficiency (PMID: 22815559, 28667724). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. 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.