ClinVar Miner

Submissions for variant NM_199292.3(TH):c.1481C>T (p.Thr494Met) (rs45471299)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622283 SCV000741297 uncertain significance Inborn genetic diseases 2018-01-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Invitae RCV000457250 SCV000553486 likely pathogenic Dystonia 2016-10-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 494 of the TH protein (p.Thr494Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs45471299, ExAC 0.01%). This variant has been reported as compound heterozygous and segregates with an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A) in a single family (PMID: 11246459). The variant segregates with disease in 2 affected brothers that inherited this variant from an unaffected father and a second variant (p.Arg337His) from an unaffected mother. In addition, this variant has been identified in the homozygous state in two unrelated individuals affected with dystonia (Invitae database). ClinVar contains an entry for this variant (Variation ID: 12326). Experimental studies have shown that this variant decreases the stability of the TH enzyme, suggesting that it has a deleterious effect on protein function (PMID: 15468323). This missense change is located in a region of the TH protein where a significant number of previously reported TH missense mutations are found (PMID: 20399390, 17696123, 20430833, 11160968). In summary, this variant is a rare missense change that has been observed in affected individuals and is likely to disrupt protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000013119 SCV000033366 pathogenic Segawa syndrome, autosomal recessive 2000-01-01 no assertion criteria provided literature only

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