Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000305413 | SCV000338648 | pathogenic | not provided | 2015-12-23 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781431 | SCV000919449 | pathogenic | Fabry disease | 2021-03-12 | criteria provided, single submitter | clinical testing | Variant summary: GLA c.422C>T (p.Thr141Ile) 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 was absent in 183470 control chromosomes (gnomAD). c.422C>T has been reported in the literature in individuals affected with Fabry Disease (example: Shabbeer_2002, Boyd_2013, Sirrs_2010, Vieitez_2018, Fuller_2005). These data indicate that the variant is likely to be associated with disease. In vitro functional studies report below level of detection (Benjamin_2016) to no enzymatic activity with/without the pharmacological chaperone 1-deoxygalactonojirimycin (DGJ) (Lukas_2013). The variant was also reported among mutations that are not amenable to Migalastat (Benjamin_2016). One other ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Revvity Omics, |
RCV000305413 | SCV002024321 | pathogenic | not provided | 2021-04-27 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV000781431 | SCV002054436 | pathogenic | Fabry disease | 2021-07-15 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000781431 | SCV002289005 | likely pathogenic | Fabry disease | 2023-12-05 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 141 of the GLA protein (p.Thr141Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 12175777, 24094560, 29631605). ClinVar contains an entry for this variant (Variation ID: 285570). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 23935525, 27657681). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |