Submissions for variant NM_024312.5(GNPTAB):c.1196C>T (p.Ser399Phe)

gnomAD frequency: 0.00001  dbSNP: rs281865026

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000820177	SCV000960877	pathogenic	Mucolipidosis type II; Pseudo-Hurler polydystrophy	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 399 of the GNPTAB protein (p.Ser399Phe). This variant is present in population databases (rs281865026, gnomAD 0.003%). This missense change has been observed in individual(s) with GNPTAB-related conditions (PMID: 16630736, 19659762, 23566849, 27710913). ClinVar contains an entry for this variant (Variation ID: 38413). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GNPTAB function (PMID: 24375680, 24550498, 25505245). For these reasons, this variant has been classified as Pathogenic.
Lifecell International Pvt. Ltd	RCV000031967	SCV003926489	pathogenic	Pseudo-Hurler polydystrophy		criteria provided, single submitter	clinical testing	A Homozygote Missense variant c.1196C>T in Exon 10 of the GNPTAB gene that results in the amino acid substitution p.Ser399Phe was identified. The variant was found in ClinVar (Variant ID: 38413) with a classification of Conflicting interpretations of pathogenicity and a review status of (1 star) criteria provided, single submitter. The observed variant has a maximum allele frequency of 0.00002/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been previously reported by Encarnação M, et al, 2009. Functional analysis showed the mutation leads to overexpression of the enzyme. (Qian Y et al, 2015) Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000031967	SCV004692830	likely pathogenic	Pseudo-Hurler polydystrophy		criteria provided, single submitter	clinical testing
GeneReviews	RCV000031967	SCV000054659	pathologic	Pseudo-Hurler polydystrophy	2012-05-10	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Natera, Inc.	RCV001831620	SCV002088593	pathogenic	Mucolipidosis type II	2020-09-10	no assertion criteria provided	clinical testing