ClinVar Genomic variation as it relates to human health

This sequence change replaces proline with arginine at codon 323 of the GLA protein (p.Pro323Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of GLA-related conditions (PMID: 26415523). ClinVar contains an entry for this variant (Variation ID: 217406). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GLA function (PMID: 26415523). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces proline with arginine at codon 323 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study has shown that this variant leads to 63% residual alpha-galactosidase A (GLA) enzyme activity in transfected cells (PMID: 26415523). This variant has been reported in one individual suspected to be affected with Fabry disease (PMID: 26415523). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This missense variant replaces proline with arginine at codon 323 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Variant summary: GLA c.968C>G (p.Pro323Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183503 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.968C>G has been reported in the literature in at-least one individual with clinical features of GLA-related condition (example: Lukas_2016) . These report(s) do not provide unequivocal conclusions about association of the variant with Fabry Disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Lukas_2016). The following publication has been ascertained in the context of this evaluation (PMID: 26415523). ClinVar contains an entry for this variant (Variation ID: 217406). Based on the evidence outlined above, the variant was classified as uncertain significance.