ClinVar Miner

Submissions for variant NM_199292.3(TH):c.1234C>A (p.Gln412Lys) (rs121917762)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229249 SCV000291894 likely pathogenic Dystonia 2016-02-06 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 412 of the TH protein (p.Gln412Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with dopa-responsive dystonia in a single family (PMID: 7814018). Specifically, this variant was found to be homozygous in two affected siblings and heterozygous in the unaffected parents. ClinVar contains an entry for this variant (Variation ID: 12324), and it is also known as Gln381Lys in the literature. Experimental studies have shown that this missense change results in decreased TH enzyme activity (PMID: 24753243, 8528210, 8817341). Furthermore, a mouse model carrying this variant recapitulates the dopa-responsive dystonia phenotype (PMID: 26220941). In summary, this variant has been observed to segregate with dopa-responsive dystonia in one family. In addition, both experimental and animal studies suggest that it impacts TH enzyme function and causes disease. For these reasons, this change has been classified as Likely Pathogenic.
OMIM RCV000013117 SCV000033364 pathogenic Segawa syndrome, autosomal recessive 1999-06-01 no assertion criteria provided literature only

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