ClinVar Miner

Submissions for variant NM_000360.4(TH):c.1400A>G (p.Asp467Gly) (rs771351747)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000364341 SCV000369908 uncertain significance Segawa syndrome, autosomal recessive 2017-04-27 criteria provided, single submitter clinical testing The TH c.1400A>G (p.Asp467Gly) missense variant has been reported in two studies in which it is found in a compound heterozygous state in three patients (including two brothers) with dopa-responsive dystonia (Furukawa et al. 2001; Schiller et al. 2004). The variant was found in a heterozygous state in two unaffected parents. The variant has also been reported in a heterozygous state in one patient with Parkinson disease (Rengmark et al. 2016). The p.Asp467Gly variant was absent from 230 controls and is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Asp467 residue is conserved and located in the tetramerization domain suggesting that the variant may exert a significant influence on oligomerization of the protein. In a study in E. Coli, the presence of the p.Asp467Gly variant resulted in a significant reduction in protein levels with less than 10% residual activity compared to wild type protein (Fossbakk et al. 2014). Based on the evidence the p.Asp467Gly variant is classified as a variant of unknown significance but suspicious for pathogenicity for tyrosine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics RCV000364341 SCV001163635 likely pathogenic Segawa syndrome, autosomal recessive criteria provided, single submitter clinical testing
Invitae RCV001051660 SCV001215828 pathogenic Dystonia 2019-04-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 498 of the TH protein (p.Asp498Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs771351747, ExAC 0.01%). This variant has been observed in individuals affected with TH-related conditions and reported to segregate with L-dopa responsive dystonia in a family (PMID: 11160968, 15505183, 15747353). ClinVar contains an entry for this variant (Variation ID: 304067). This variant has been reported to affect TH protein function (PMID: 24753243). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000364341 SCV000790903 likely pathogenic Segawa syndrome, autosomal recessive 2017-05-12 no assertion criteria provided clinical testing

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