ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.1088G>A (p.Arg363His) (rs111422676)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724675 SCV000331853 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000398396 SCV000695730 pathogenic Fabry disease 2017-07-05 criteria provided, single submitter clinical testing Variant summary: The GLA c.1088G>A (p.Arg363His) variant involves the alteration of a non-conserved nucleotide. 2/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/88023 control chromosomes (3 hemizygotes) at a frequency of 0.0000341, which does not exceed the estimated maximal expected allele frequency of a pathogenic GLA variant (0.005). This variant has been reported in multiple patients with classic or late-onset Fabry disease. In vitro enyzme activity assay showed this variant led to moderate decrease of enzyme activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. In addition, p.R363C and p.R363P have been reported to associate with Fabry disease, suggesting R363 is critical for GLA function. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000398396 SCV000893811 pathogenic Fabry disease 2018-10-31 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000398396 SCV000993560 pathogenic Fabry disease 2018-10-10 criteria provided, single submitter research
Gharavi Laboratory,Columbia University RCV000724675 SCV000920679 uncertain significance not provided 2018-09-16 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV000398396 SCV001422922 likely pathogenic Fabry disease 2020-01-22 no assertion criteria provided curation The p.Arg363His variant in GLA has been reported in at least eight individuals with Fabry disease (PMID: 30477121, 21420783, 11668641, 12175777, 23935525, 28360401, 28302345), segregated with disease in three affected relatives from one family (PMID: 26937405), and has been identified in 0.03% (5/19142) of South Asian chromosomes, including 3 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111422676). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Additionally, this variant has a high prevalence in late-onset cases, which may account for the frequency in gnomAD. This variant has also been reported in ClinVar as Pathogenic by EGL Genetic Diagnostics and Integrated Genetics (Variation ID: 222141). In vitro functional studies provide some evidence that the p.Arg363His variant may slightly impact protein function (PMID: 21598360, 23935525, 19387866). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of individuals hemizygous for this variant is highly specific for Fabry disease based on enzymatic diagnosis consistent with disease (PMID: 30477121, 21420783, 11668641, 12175777, 23935525, 28360401, 28302345). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic despite the higher than expected allele frequency in the general population. ACMG/AMP Criteria applied: BS1_supporting, PP1_moderate, PP4, PS3_supporting, PS4_moderate (Richards 2015).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.