Submissions for variant NM_024312.5(GNPTAB):c.1774G>A (p.Ala592Thr)

gnomAD frequency: 0.00006  dbSNP: rs149390820

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000087103	SCV000915567	uncertain significance	Pseudo-Hurler polydystrophy	2018-11-07	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001110795	SCV001268276	uncertain significance	Mucolipidosis type II	2017-04-28	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228331	SCV002511875	uncertain significance	not specified	2022-04-21	criteria provided, single submitter	clinical testing	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.
Invitae	RCV002514535	SCV003466533	uncertain significance	Mucolipidosis type II; Pseudo-Hurler polydystrophy	2022-06-11	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV003332114	SCV004039787	uncertain significance	not provided	2023-09-30	criteria provided, single submitter	clinical testing	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)
Mayo Clinic Laboratories, Mayo Clinic	RCV003332114	SCV004226630	likely pathogenic	not provided	2022-02-09	criteria provided, single submitter	clinical testing	PM2, PS3
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001110795	SCV004805606	uncertain significance	Mucolipidosis type II	2024-03-25	criteria provided, single submitter	research
Unidad de Diagnostico y Tratamiento de Errores Congenitos del Metabolismo. Hospital Clínico Universitário de Santiago de Compostela	RCV000087103	SCV000119960	pathogenic	Pseudo-Hurler polydystrophy		no assertion criteria provided	research