ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.593T>C (p.Ile198Thr) (rs727503950)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Albrecht-Kossel-Institute,Medical University Rostock RCV000153323 SCV000246053 likely pathogenic Fabry disease 2014-01-01 no assertion criteria provided research
Albrecht-Kossel-Institute,Medical University Rostock RCV000209729 SCV000246054 drug response Deoxygalactonojirimycin response 2014-01-01 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723576 SCV000202803 likely pathogenic not provided 2017-10-24 criteria provided, single submitter clinical testing
Invitae RCV000153323 SCV000819448 uncertain significance Fabry disease 2018-04-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 198 of the GLA protein (p.Ile198Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Fabry disease (PMID: 25149322). This variant has also been observed in an individual with reduced GLA enzymatic activity, findings that are highly specific for Fabry disease (PMID: 21587323). ClinVar contains an entry for this variant (Variation ID: 167142). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Experimental studies have shown that this missense change decreases GLA enzyme activity in vitro (PMID: 26415523). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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