ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Integrated Genetics/Laboratory Corporation of America RCV000153323 SCV001362671 likely pathogenic Fabry disease 2019-12-31 criteria provided, single submitter clinical testing Variant summary: GLA c.593T>C (p.Ile198Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 181907 control chromosomes (gnomAD). c.593T>C has been reported in the literature in individuals affected with Fabry Disease (e.g. Auray-Blais_2010, Germain_2014, Pettazzoni_2017) and in a 16 year old male with reduced Alpha-Galactosidase A activity but no indications of clinical disease (Houge_2011). These data indicate that the variant is likely to be associated with disease. In in vitro experimental studies, the variant shows reduced GLA enzymatic activity compared to wild-type (Lukas_2016, Oommen_2019) .Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
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
Broad Institute Rare Disease Group,Broad Institute RCV000153323 SCV001422641 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided curation The p.Ile198Thr variant in GLA has been reported in 2 males and 2 females with Fabry disease (PMID: 26415523, 25974833, 21587323), and has been identified in 0.0025% (2/81184) of European (non-Finnish) chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727503950). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as likely pathogenic by EGL Genetic Diagnostics and the Albrecht-Kossel-Institute, and as a VUS by Invitae (Variation ID: 167142). In vitro functional studies provide some evidence that the p.Ile198Thr variant may slightly impact protein function (PMID: 26415523). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant will impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based the on classical phenotype consistent with disease (PMID: 21587323, 25149322, 26415523). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting, PP4, PS3_supporting, PS4_supporting (Richards 2015).

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