Total submissions: 16
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV000723576 | SCV007579688 | uncertain significance | not provided | 2025-11-06 | criteria provided, single submitter | clinical testing | PM1_supporting, PM2, PS3_supporting, PP3 |
| Natera, |
RCV000153323 | SCV007531293 | likely pathogenic | Fabry disease | 2025-09-01 | criteria provided, single submitter | clinical testing | The c.593T>C variant in GLA is a missense variant predicted to cause substitution of isoleucine to threonine at amino acid 198. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in at least one unaffected individual, with a zygosity that is consistent with the inheritance pattern for the associated condition (in gnomAD and/or literature). This variant has been observed in affected individual(s) with monoallelic occurrence (heterozygous/hemizygous) (PMID: 25974833, 25149322, 28749998, 25511234, 38739391). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Likely Pathogenic. |
| Genomenon, |
RCV000153323 | SCV006336154 | likely pathogenic | Fabry disease | 2025-09-19 | criteria provided, single submitter | curation | GLA c.593T>C is a missense variant that changes the amino acid at residue 198 from Isoleucine to Threonine. This variant has been observed in at least one proband affected with Fabry disease (PMID:35977816;39343861;25974833;39669636;26415523;36156392;28749998;21587323). Functional studies have been reported; however, the significance of the findings remain unclear and/or were performed in patient cells (PMID:32023956;31036492;26415523;25974833;32802993;21587323;27657681;39343861). It is absent or not present at a significant frequency in gnomAD. In silico models agree that this variant is possibly or probably damaging. In conclusion, we classify GLA c.593T>C as a likely pathogenic variant. |
| Ce |
RCV000723576 | SCV005894403 | likely pathogenic | not provided | 2025-01-01 | criteria provided, single submitter | clinical testing | GLA: PM1, PM2, PS4:Moderate, PS3:Supporting |
| Ambry Genetics | RCV002354357 | SCV002647545 | uncertain significance | Cardiovascular phenotype | 2024-09-10 | criteria provided, single submitter | clinical testing | The p.I198T variant (also known as c.593T>C), located in coding exon 4 of the GLA gene, results from a T to C substitution at nucleotide position 593. The isoleucine at codon 198 is replaced by threonine, an amino acid with similar properties. This variant was first reported in a sample from a male kidney donor with reduced alpha-galactosidase enzyme activity for whom kidney biopsy was abnormal (Houge G et al. Eur. J. Hum. Genet., 2011 Nov;19:1111). This variant has been detected in additional Fabry disease cohorts in individuals with reduced but residual enzyme activity; however, clinical details were limited and no individuals with classic Fabry disease were apparent (Auray-Blais C et al. Clin. Chim. Acta, 2015 Jan;438:195-204; Echevarria L et al. Clin. Genet., 2016 Jan;89:44-54; Pettazzoni M et al. PLoS ONE, 2017 Jul;12:e0181700). One study indicated this variant to result in reduced enzyme activity in vitro (Lukas J et al. Hum. Mutat., 2016 Jan;37:43-51). Based on data from gnomAD, the C allele has an overall frequency of 0.0011% (2/181907) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0025% (2/81184) of European (Non-Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Genome- |
RCV000153323 | SCV002054814 | pathogenic | Fabry disease | 2021-07-15 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV000723576 | SCV002018457 | likely pathogenic | not provided | 2025-06-23 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000723576 | SCV001822500 | uncertain significance | not provided | 2025-10-10 | criteria provided, single submitter | clinical testing | Identified in multiple unrelated individuals with reduced alpha galactosidase activity; however many of these individuals were asymptomatic and limited clinical information was provided on individuals described as symptomatic (PMID: 25149322, 21587323, 25511234, 25974833, 28749998, 39343861); Functional analysis of p.(I198T) found that it is associated with significant residual enzyme activity (39-65%) (PMID: 27657681, 26415523, 31036492); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25511234, 26415523, 25974833, 21587323, 31036492, 35977816, 32161151, 36156392, 37441486, 29476735, 38531466, 39669636, 38739391, Chen-Deutsch[abstract], 28749998, 32802993, 31996269, 39343861, 25149322, 27657681, 40840051) |
| Color Diagnostics, |
RCV000153323 | SCV001735629 | uncertain significance | Fabry disease | 2025-06-30 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with threonine at codon 198 in the substrate binding region of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. Functional studies have shown that the variant may retain significant residual GLA enzyme activity in the range of 35%-60% compared to the wild type (PMID: 26415523, 31036492). This variant has been reported in individuals, both male and female, affected with Fabry disease (PMID: 21587323, 25511234, 25974833). It has also been reported in both infant and adult individuals with suspected diagnoses of Fabry disease (PMID: 25149322, 26415523, 31996269, 32802993, 36156392). It has been shown that this variant segregates with disease in five affected individuals from one family (PMID: 21587323). This variant has been identified in 2/181907 chromosomes, including 1 hemizygote, in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Broad Center for Mendelian Genomics, |
RCV000153323 | SCV001422641 | uncertain significance | Fabry disease | 2020-01-22 | criteria provided, single submitter | 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). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000153323 | SCV001362671 | pathogenic | Fabry disease | 2025-09-30 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 1.1e-05 in 181907 control chromosomes. c.593T>C has been observed in multiple individuals affected with Fabry Disease (e.g. Auray-Blais_2015, Lukas_2016, Germain_2014, Pettazzoni_2017, Varela_2020, internal_data). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Lukas_2016, Oommen_2019). The most pronounced variant effect results in 30%-50% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 26415523, 25974833, 25511234, 25149322, 29476735, 21587323, 31036492, 28749998, 31996269). ClinVar contains an entry for this variant (Variation ID: 167142). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Labcorp Genetics |
RCV000153323 | SCV000819448 | pathogenic | Fabry disease | 2026-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 198 of the GLA protein (p.Ile198Thr). This variant is present in population databases (rs727503950, gnomAD 0.003%). This missense change has been observed in individual(s) with Fabry disease (PMID: 21587323, 25149322, 25974833; internal data). ClinVar contains an entry for this variant (Variation ID: 167142). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 26415523). For these reasons, this variant has been classified as Pathogenic. |
| Eurofins Ntd Llc |
RCV000723576 | SCV000202803 | likely pathogenic | not provided | 2017-10-24 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004752760 | SCV005364770 | uncertain significance | GLA-related disorder | 2024-03-22 | no assertion criteria provided | clinical testing | The GLA c.593T>C variant is predicted to result in the amino acid substitution p.Ile198Thr. This variant has been reported in individuals with reduced blood leukocyte alpha-galactosidase A enzyme activity both with and without clinical features of Fabry disease, suggesting it may have reduced penetrance or represent a pseudodeficiency allele (Echevarria et al. 2015. PubMed ID: 25974833; Houge et al. 2011. PubMed ID: 21587323; Pettazoni et al. 2017. PubMed ID: 28749998; Germain et al. 2015. PubMed ID: 25511234; Table S1, Auray-Blais et al. 2015. PubMed ID: 25149322). In vitro functional studies also showed this variant resulted in moderately reduced enzyme activity 40-64% of wild type (Lukas et al. 2015. PubMed ID: 26415523; Table S1, Benjamin et al. 2017. PubMed ID: 27657681). This variant is listed in ClinVar with conflicting interpretations of uncertain, likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/167142/). This variant is reported in 0.0025% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Albrecht- |
RCV000209729 | SCV000246054 | drug response | Migalastat response | 2014-01-01 | no assertion criteria provided | research | |
| Albrecht- |
RCV000153323 | SCV000246053 | likely pathogenic | Fabry disease | 2014-01-01 | no assertion criteria provided | research |