ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate a damaging effect with significant reduction of enzyme function for the A592T mutant (PMID: 25505245); This variant is associated with the following publications: (PMID: 34426522, 31589614, 25505245, 24767253)

PM2, PS3

The GNPTAB c.1774G>A (p.Ala592Thr) variant is a missense variant that has been reported in one study in which it is found in one individual affected with mucolipidosis III alpha/beta in a compound heterozygous state with a second missense variant (Fernández-Marmiesse et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00025 in the European (non-Finnish) population of the Exome Aggegation Consortium. The p.Ala592Thr variant is located in the spacer domain. Functional studies conducted in HEK293 cells showed the variant reduced GlcNAc-1-phosphotransferase activity to approximately 25% of the wild type level (Qian et al. 2015). Based on the evidence, the p.Ala592Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for GNPTAB-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Variant summary: GNPTAB c.1774G>A (p.Ala592Thr) 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 9.5e-05 in 251440 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GNPTAB causing Mucolipidosis (9.5e-05 vs 0.0022), allowing no conclusion about variant significance. c.1774G>A has been reported in the literature as a compound heterozygous genotype in at-least one comprehensively genotyped individual affected with Mucolipidosis (example, Fernandez-Marmiesse_2014). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Qian_2015). The most pronounced variant effect results in 23% of normal Phosphotransferase activity in vitro and predominant localization within the Golgi complex. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 592 of the GNPTAB protein (p.Ala592Thr). This variant is present in population databases (rs149390820, gnomAD 0.02%). This missense change has been observed in individual(s) with mucolipidosis type II and mucolipidosis type III (PMID: 24767253). ClinVar contains an entry for this variant (Variation ID: 100737). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GNPTAB function (PMID: 25505245). 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.