ClinVar Miner

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

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Total submissions: 9
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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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Baylor Genetics RCV000398396 SCV001522947 pathogenic Fabry disease 2020-11-20 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV000398396 SCV001588429 pathogenic Fabry disease 2020-09-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 363 of the GLA protein (p.Arg363His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs111422676, ExAC 0.03%). This variant has been observed in individuals with Fabry disease (PMID: 26937405, 11668641, 28302345, 12175777). ClinVar contains an entry for this variant (Variation ID: 222141). This variant has been reported to affect GLA protein function (PMID: 19387866, 21598360). This variant disrupts the p.Arg363Cys amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12175777, 21598360, 25835592, 26937405, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd,Neuberg Centre for Genomic Medicine RCV000398396 SCV001712060 pathogenic Fabry disease criteria provided, single submitter clinical testing The missense variant p.R363H in GLA (NM_000169.2) has been reported previously in affected individuals with late onset Fabry disease (Blaydon et al 2001; Serebrinsky et al, 2015). In vitro enzyme studies depict a moderate effect on enzyme activity which leads to an attenuated/atypical/late-onset phenotype (Lukas et al, 2013; Riera et al, 2015). I t has been classified as a Pathogenic for the late onset phenotype by the Fabry disease working group (Germain et al,2 020). It has been submitted to ClinVar with conflicting interpretations including VUS/Likely Pathogenic and Pathogenic. It is present in 6 hemizygous males in the gnomAD database. However presence of clinical variability ranging from single organ involvement to ascertainment via family screening could account for the presence of these hemizygous males within the gnomAD database. There is a small physicochemical difference between arginine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. In silico tools predict the variant to be tolerated and the residue is weakly conserved across species. For these reasons, this variant has been classified as Pathogenic
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).

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