Submissions for variant NM_000360.4(TH):c.1228C>T (p.Arg410Trp)

dbSNP: rs575326605

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695395	SCV000823892	pathogenic	Autosomal recessive DOPA responsive dystonia	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 441 of the TH protein (p.Arg441Trp). This variant is present in population databases (rs575326605, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of TH-related dystonia (PMID: 27619486, 37840187; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1228C>T . ClinVar contains an entry for this variant (Variation ID: 573670). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TH protein function with a positive predictive value of 80%. This variant disrupts the p.Arg441 amino acid residue in TH. Other variant(s) that disrupt this residue have been observed in individuals with TH-related conditions (PMID: 23939262, 27619486), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001585632	SCV001821237	uncertain significance	not specified	2021-08-12	criteria provided, single submitter	clinical testing	Variant summary: TH c.1321C>T (p.Arg441Trp) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 248838 control chromosomes, predominantly at a frequency of 0.0013 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TH causing Autosomal Recessive Segawa Syndrome, DOPA responsive dystonia phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1321C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with DOPA responsive dystonia (Segawa Syndrome, Autosomal Recessive)(example, Yan_2017). Another individual with DOPA responsive dystonia and a compound heterozygous genotype including a different variant at the same codon, c.1322G>C (p.R441P) has also been reported (example, Haugarvoll_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. These data do not allow any conclusion about variant significance. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneDx	RCV001756201	SCV001988436	uncertain significance	not provided	2019-10-26	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27619486)
Fulgent Genetics, Fulgent Genetics	RCV000695395	SCV002792035	likely pathogenic	Autosomal recessive DOPA responsive dystonia	2024-04-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000695395	SCV004203841	likely pathogenic	Autosomal recessive DOPA responsive dystonia	2024-03-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000695395	SCV004238760	likely pathogenic	Autosomal recessive DOPA responsive dystonia	2023-04-11	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000695395	SCV005401027	likely pathogenic	Autosomal recessive DOPA responsive dystonia		criteria provided, single submitter	clinical testing	The observed missense c.1228C>T(p.Arg410Trp) / c.1321C>T (p.Arg441Trp) variant in TH gene has been reported previously in individual(s) affected with TH associated Segawa Syndrome (Yan YP, et al., 2017). The p.Arg410Trp variant has been reported with allele frequency of 0.02% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic / Uncertain Significance (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on TH gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 410 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. Another missense variant [c.1322G>C (p.Arg441Pro] on the same residue of this gene has previously been reported to be disease causing (Haugarvoll K & Bindoff LA., 2011), suggesting that this residue might be of clinical significance. For these reasons, this variant has been classified as Likely Pathogenic.
Athena Diagnostics	RCV001756201	SCV005622081	uncertain significance	not provided	2024-09-30	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. This variant segregates with disease in at least one family. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein.
Natera, Inc.	RCV000695395	SCV002091035	uncertain significance	Autosomal recessive DOPA responsive dystonia	2020-03-06	no assertion criteria provided	clinical testing