ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.335G>A (p.Arg112His) (rs372966991)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723466 SCV000227043 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000175540 SCV000695739 pathogenic Fabry disease 2020-07-08 criteria provided, single submitter clinical testing Variant summary: GLA c.335G>A (p.Arg112His) 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 183395 control chromosomes (gnomAD). The variant, c.335G>A, has been reported in the literature in several individuals affected with Fabry Disease (e.g. Schafer_2005, Shimotori_2007, Sirrs_2010, vanderTol_2016, Weidemann_2020). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated significantly reduced (i.e. less than 10% of normal) GLA activity in both patient derived samples and in in vitro studies, and the enzyme activity was shown to be responsive to 1-deoxygalactonojirimycin (DGJ) treatment in vitro (e.g. Ishii_2007, Shimotori_2007, Lukas_2013). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (4x) or likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000175540 SCV000893813 pathogenic Fabry disease 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000175540 SCV000913664 likely pathogenic Fabry disease 2019-03-22 criteria provided, single submitter clinical testing
Invitae RCV000175540 SCV000949841 pathogenic Fabry disease 2019-08-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 112 of the GLA protein (p.Arg112His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs372966991, ExAC 0.002%). This variant has been observed in individuals affected with Fabry disease (PMID: 25040344, 18205205, 7531540, 25026990, 17532296, 18205205). ClinVar contains an entry for this variant (Variation ID: 195028). Experimental studies have shown that this missense change results in a GLA protein with significantly reduced enzymatic activity (PMID: 17555407, 23935525, 21598360). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000175540 SCV001365616 pathogenic Fabry disease 2019-11-20 criteria provided, single submitter clinical testing The p.Arg112His variant in GLA has been reported in at least 8 individuals with either classic or atypical Fabry disease and segregated with disease in 2 affected male relatives from 2 families (Eng 1994, Shimotori 2008, Sirrs 2010, Gaggl 2013, Nishida 2014, Sechi 2014, Smid 2015, Arends 2017). This variant has been identified in 2/81850 European chromosomes by gnomAD ( and is reported by other clinical laboratories in ClinVar (Variation ID: 195028). Functional studies demonstrate that this variant is associated with reduced enzyme activity in patient samples (Nishida 2014) and in a transfected cell line (Shin 2007). Computational prediction tools and conservation analyses are consistent with pathogenicity. Additionally, a pathogenic variant at the same position, p.Arg112Cys, has been identified in patients with classic Fabry disease, suggesting that changes at this position may not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for X-linked Fabry disease. ACMG/AMP Criteria applied: PS4, PM2, PM5, PS3_Moderate, PP1, PP3.
Counsyl RCV000175540 SCV001132403 likely pathogenic Fabry disease 2017-03-21 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000175540 SCV001423099 pathogenic Fabry disease 2020-01-22 no assertion criteria provided curation The p.Arg112His variant in GLA has been reported in over 15 individuals with Fabry Disease, segregated with disease in three affected relatives from one family (PMID: 25040344, 27831900, 25040344, 25026990, 23913314, 7531540, 17532296, 18205205, 17555407), and has been identified in 0.0024% (2/81850) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs372966991). 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 pathogenic by EGL Genetic Diagnostics and Integrated Genetics (Variation ID: 195028). In vitro functional studies provide some evidence that the p.Arg112His variant may slightly impact protein function (PMID: 30386727, 27896103, 18205205, 23935525, 17532296, 17555407). 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 on the classical phenotype consistent with disease (PMID: 27831900, 25040344, 25026990, 23913314, 7531540, 17532296, 18205205, 17555407). The p.Arg112His is located in a region of GLA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 27896103, 17555407). Two additional pathogenic variants, causing a different amino acid change at the same position, (p.Arg112Cys, p.Arg112Leu), have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 1315715, 23935525, 14635108/Variation ID: 92550, 92551). In summary, this variant meets criteria to be classified as pathogenic for Fabry disease in an X-linked manner based on the prevalence of the variant in affected individuals, its absence from population databases, computational evidence suggesting the variant is deleterious, and functional studies with decreased enzyme activity. ACMG/AMP Criteria applied: PS4, PM5, PM2_supporting, PP3_moderate, PP1, PP4, PS3_supporting, PM1_supporting (Richards 2015).

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