Submissions for variant NM_000360.4(TH):c.364C>T (p.Arg122Ter)

gnomAD frequency: 0.00002  dbSNP: rs771610752

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521520	SCV000616894	pathogenic	not provided	2018-04-13	criteria provided, single submitter	clinical testing	The R153X variant in the TH gene has been reported previously in association with autosomal recessive tyrosine hydroxylase deficiency (Mak et al., 2010; Chi et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R153X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R153X as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671827	SCV000947427	pathogenic	Autosomal recessive DOPA responsive dystonia	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg153*) in the TH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TH are known to be pathogenic (PMID: 22264700, 24753243). This variant is present in population databases (rs771610752, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with tyrosine hydroxylase deficiency (PMID: 20056467, 22264700, 28087438). ClinVar contains an entry for this variant (Variation ID: 449110). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000671827	SCV002058733	pathogenic	Autosomal recessive DOPA responsive dystonia	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000059, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000449110, PMID:20056467). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV000671827	SCV002775284	pathogenic	Autosomal recessive DOPA responsive dystonia	2022-05-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000671827	SCV000796850	pathogenic	Autosomal recessive DOPA responsive dystonia	2018-01-02	no assertion criteria provided	clinical testing
SingHealth Duke-NUS Institute of Precision Medicine	RCV000671827	SCV000853144	likely pathogenic	Autosomal recessive DOPA responsive dystonia	2017-06-07	no assertion criteria provided	curation
Natera, Inc.	RCV000671827	SCV001463820	pathogenic	Autosomal recessive DOPA responsive dystonia	2020-09-16	no assertion criteria provided	clinical testing