Submissions for variant NM_000169.3(GLA):c.593T>C (p.Ile198Thr)

gnomAD frequency: 0.00002  dbSNP: rs727503950

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723576	SCV000202803	likely pathogenic	not provided	2017-10-24	criteria provided, single submitter	clinical testing
Invitae	RCV000153323	SCV000819448	pathogenic	Fabry disease	2024-01-19	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; Invitae). ClinVar contains an entry for this variant (Variation ID: 167142). 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: 26415523). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000153323	SCV001362671	likely pathogenic	Fabry disease	2022-09-16	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 (1). two individuals affected with later onset Fabry Disease, one of whom was reported as having no angiokeratoma but evidence of vascular disease (example, Germain_2014, Pettazzoni_2017), (2). in a 6.4 year old male with Fabry disease from a cohort of treated and untreated pediatric and adult Fabry patients (example, Auray-Blais_2015), (3). in a male patient characterized enzymatically as having a later onset Fabry disease (i.e., >20% WT activity levels) and a slight elevation in Lyso-Gb3 levels (example, Lukas_2016), (4). in a male with a suspected phenotype of later onset Fabry disease (Varela_2020), (5). in two heterozygous females affected with Fabry disease who displayed random X-chromosome inactivation and alpha galctodisease activity levels of 27 and 46% of WT (Echevarria_2016), and (6). in a 16 year old male kidney donor with reduced plasma Alpha-Galactosidase A activity (<10% of WT), large and constant amounts of Fabry-specific lipid deposits, mainly in podocytes from graft biopsy samples analyzed at transplantation and at 3 and 12 years of age, but no other indications of clinical disease (Houge_2011). Based on evaluation and analysis of the clinically unaffected mother and sisters, this patient reported by Houge_2011 was characterized by the authors as having a non-penetrant biochemically true positive but clinically false-positive allele. These data indicate that the variant is a mild and/or incompletely penetrant allele that is likely to be associated with disease. Multiple publications report conflicting experimental evidence evaluating an impact on protein function depending upon the specimen type and/or the in-vitro experimental system utilized (example, Houge_2011, Lukas_2016, Echevarria_2016, Oommen_2019). The most pronounced variant effect varies from <10% of normal alpha galactosidase activity in a male donor plasma specimen (Houge_2011), 38.7% of normal activity in a transiently expressed HEK 293H cell system (Lukas_2016), 27% and 46% of normal activity levels respectively in peripheral blood leukocytes from two heterozygous females with random X-chromosome inactivation (Echevarria_2016) and 58.3% of normal activity in a validated human embryonic kidney cell (HEK) based amenability assay (Oommen_2019). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=3, Likely Pathogenic/Pathogenic, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic for a later onset/mild/variably penetrant phenotype of Fabry Disease.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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).
Color Diagnostics, LLC DBA Color Health	RCV000153323	SCV001735629	uncertain significance	Fabry disease	2022-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 198 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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 affected with Fabry disease (PMID: 21587323, 25511234, 25974833). It has also been reported in individuals with suspected diagnoses of Fabry disease (PMID: 25149322, 26415523, 31996269, 32802993). It has been shown that this variant segregates with disease in 5 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.
GeneDx	RCV000723576	SCV001822500	uncertain significance	not provided	2023-06-26	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 (Houge G et al., 2011; Auray-Blais C et al., 2015; Germain DP et al., 2015 Echevarria L et al., 2016); Functional analysis of p.(I198T) found that it is associated with significant residual enzyme activity (39-65%) (Lukas J et al., 2016; Benjamin ER et a., 2017); 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, 27657681, 25149322, 31036492, 35977816, 32161151, 36156392)
Revvity Omics, Revvity	RCV000723576	SCV002018457	likely pathogenic	not provided	2023-12-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000153323	SCV002054814	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354357	SCV002647545	uncertain significance	Cardiovascular phenotype	2022-07-07	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.
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	Migalastat response	2014-01-01	no assertion criteria provided	research