Submissions for variant NM_000360.4(TH):c.1358G>A (p.Arg453His)

gnomAD frequency: 0.00009  dbSNP: rs759599321

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000994542	SCV001148141	uncertain significance	not provided	2018-10-01	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV001809883	SCV002059166	likely pathogenic	Autosomal recessive DOPA responsive dystonia	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TH related disorder (PMID:25181484, PS1_P). The variant was co-segregated with Segawa syndrome, recessive in multiple affected family members (PMID: 25181484, PP1_P). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product(PMID: 25181484, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.973, 3CNET: 0.99, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000068, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001809883	SCV002308896	likely pathogenic	Autosomal recessive DOPA responsive dystonia	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 484 of the TH protein (p.Arg484His). This variant is present in population databases (rs759599321, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with dopa responsive dystonia (PMID: 25181484). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg453His. ClinVar contains an entry for this variant (Variation ID: 806594). 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) has been performed 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. Experimental studies have shown that this missense change affects TH function (PMID: 25181484). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298813	SCV002599038	uncertain significance	not specified	2022-09-22	criteria provided, single submitter	clinical testing	Variant summary: TH c.1451G>A (p.Arg484His) 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 allele was found at a frequency of 6.9e-05 in 203112 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not higher than predicted for a pathogenic variant in TH causing Segawa Syndrome, Autosomal Recessive (6.9e-05 vs 0.0011), allowing no conclusion about variant significance. c.1451G>A has been reported in the literature in two siblings affected with Dopa-Responsive Dystonia with a non-informative genotype (pathogenicity of the second allele is not certain) (example: Sun_2014). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (example: Sun_2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV001809883	SCV005676240	likely pathogenic	Autosomal recessive DOPA responsive dystonia	2024-06-13	criteria provided, single submitter	clinical testing