Submissions for variant NM_024312.5(GNPTAB):c.2956C>T (p.Arg986Cys)

gnomAD frequency: 0.00001  dbSNP: rs769587233

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	RCV000449553	SCV000537773	likely pathogenic	Mucolipidosis type II; Pseudo-Hurler polydystrophy	2016-01-01	criteria provided, single submitter	research
Invitae	RCV000449553	SCV001576811	pathogenic	Mucolipidosis type II; Pseudo-Hurler polydystrophy	2023-08-18	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs769587233, gnomAD 0.006%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GNPTAB function (PMID: 24375680, 25505245). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNPTAB protein function. ClinVar contains an entry for this variant (Variation ID: 397568). This missense change has been observed in individual(s) with GNPTAB-related conditions (PMID: 22495880, 32651481, 33000604; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 986 of the GNPTAB protein (p.Arg986Cys).
Myriad Genetics, Inc.	RCV000449553	SCV002060033	likely pathogenic	Mucolipidosis type II; Pseudo-Hurler polydystrophy	2021-11-19	criteria provided, single submitter	clinical testing	NM_024312.4(GNPTAB):c.2956C>T(R986C) is a missense variant classified as likely pathogenic in the context of GNPTAB-related disorders. R986C has been observed in cases with relevant disease (PMID: 24798265, 32651481, Carboni_2020_(no PMID; abstract)). Functional assessments of this variant are available in the literature (PMID: 31579991, 24375680, 25505245, DePace_2014_(no PMID; thesis), da_Silva_2011_(no PMID; abstract)). R986C has been observed in population frequency databases (gnomAD: EAS 0.006%). In summary, NM_024312.4(GNPTAB):c.2956C>T(R986C) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469150	SCV002766457	pathogenic	Mucolipidosis	2022-11-16	criteria provided, single submitter	clinical testing	Variant summary: GNPTAB c.2956C>T (p.Arg986Cys) results in a non-conservative amino acid change located in the Stealth protein CR3, conserved region 3 (IPR031357) of 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 4e-06 in 251260 control chromosomes (gnomAD). c.2956C>T has been reported in the literature as a homozygous genotype in multiple individuals affected with Mucolipidosis (Coutinho_2012, Pasumarthi_2020 and Cobos_2015). These data indicate that the variant is very likely to be associated with disease. Several publications reports experimental evidence evaluating an impact on protein function indicating that this variant results in almost abolishing the phosphotransferase activity (Qian_2015, Danyukova_2020 and DePace_2014). Three 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV003221982	SCV003915850	pathogenic	Mucolipidosis type II	2023-04-13	criteria provided, single submitter	clinical testing	A Heterozygous variation in exon 15 of the GNPTAB was detected. The observed variant c.2956C>T has not been reported in the 1000 genomes and has a MAF of 0.0004% databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 and damaging by SIFT and MutationTaster. In summary, the variant meets our criteria to be classified as pathogenic.