ClinVar Miner

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

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Total submissions: 5
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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 2016-08-02 criteria provided, single submitter clinical testing Variant summary: The GLA c.335G>A (p.Arg112His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/87742 control chromosomes at a frequency of 0.0000114, which does not exceed the estimated maximal expected allele frequency of a pathogenic GLA variant (0.005). The variant has been reported in numerous affected individuals in the literature, and the variant has been shown to have significantly reduced GLA activity in both patients and in vitro studies (Ishii_2007, Shimotori_2007). In addition, one clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, without evidence to independently evaluate. Taken together, this variant is 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 2018-09-06 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant replaces arginine with histidine at codon 112 of the GLA protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. This variant has been reported in hemizygous males presenting with non-classical, variant Fabry disease phenotype, although their GLA enzyme activity was significantly reduced and was in the range observed with classical Fabry disease (e.g. <3-5%) (PMID: 17555407, 18205205, 25040344, 25026990). An experimental study has suggested that this variant may cause the mutant protein to become unstable (PMID: 17555407). This variant has been identified in 3/178683 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variant occurring at the same amino acid, p.Arg112Cys, has been shown to cause significantly reduced GLA activity and has been associated with classical Fabry disease phenotype. Although additional studies are required to fully establish its clinical significance, based on current evidence this variant is likely pathogenic for mild or atypical Fabry disease.
Invitae RCV000175540 SCV000949841 pathogenic Fabry disease 2018-09-19 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.

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