ClinVar Miner

Submissions for variant NM_199292.3(TH):c.698G>A (p.Arg233His) (rs80338892)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000013120 SCV000678154 pathogenic Segawa syndrome, autosomal recessive 2015-09-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724645 SCV000700791 pathogenic not provided 2016-11-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000013120 SCV000893876 pathogenic Segawa syndrome, autosomal recessive 2018-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000013120 SCV000041739 pathologic Segawa syndrome, autosomal recessive 2008-02-08 no assertion criteria provided curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000013120 SCV000914501 pathogenic Segawa syndrome, autosomal recessive 2018-08-14 criteria provided, single submitter clinical testing The TH c.605G>A (p.Arg202His) missense variant, also referred to as p.Arg233His, has been reported in at least five studies in which it is reported in eight homozygotes, including two siblings (van den Heuvel et al. 1998; Najmabadi et al. 2011; Tan et al. 2014; Molero-Luis et al. 2013). Phenotypes of the individuals carrying the variant include L-DOPA-responsive dystonia (DRD), intellectual disability, unexplained dystonia without intellectual disability, and neurological disorders (van den Heuvel et al. 1998; Najmabadi et al. 2011; Tan et al. 2014; Molero-Luis et al. 2013). One homozygote with autosomal recessive intellectual disability identified in Najmabadi et al. (2011), also carried homozygous variants in seven other genes. The p.Arg202His variant was absent from 350 controls and is reported at a frequency of 0.000374 in the East Asian population of the Genome Aggregation Database. Fossbakk et al. (2014) performed thermal and kinetic analysis in E. coli and found that thermal stability was slightly reduced and residual activity of the variant protein was 14% of wild type. Based on the evidence, the p.Arg202His variant is classified as pathogenic for tyrosine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000689665 SCV000817328 pathogenic Dystonia 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 233 of the TH protein (p.Arg233His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs80338892, ExAC 0.02%). This variant has been reported to be homozygous or compound heterozygous in many individuals affected with tyrosine hydroxylase (TH) deficiency (PMID: 9703425, 10407773, 20430833, 20823027). ClinVar contains an entry for this variant (Variation ID: 12327). Experimental studies have shown that this missense change leads to decreased substrate specificity and TH enzyme activity (PMID: 24753243, 20492352, 26276013). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013120 SCV000033367 pathogenic Segawa syndrome, autosomal recessive 1999-06-01 no assertion criteria provided literature only
SingHealth Duke-NUS Institute of Precision Medicine RCV000013120 SCV000853117 pathogenic Segawa syndrome, autosomal recessive 2017-06-07 no assertion criteria provided curation

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