Submissions for variant NM_000263.4(NAGLU):c.874G>A (p.Gly292Arg)

gnomAD frequency: 0.00001  dbSNP: rs1358994052

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668384	SCV000792975	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-07-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855498	SCV002231932	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 292 of the NAGLU protein (p.Gly292Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 9950362, 10094189, 11153910, 14984474, 22976768, 23380547, 27590925, 30809705). ClinVar contains an entry for this variant (Variation ID: 553021). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NAGLU protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000668384	SCV003926592	pathogenic	Mucopolysaccharidosis, MPS-III-B	2023-05-25	criteria provided, single submitter	clinical testing	A homozygous variation in exon 5 of the NAGLU gene that results in the amino acid substitution of arginine for glycine at codon 292 was detected. The observed variant c.874G>A (p.Gly292Arg) has not beeen reported in the 1000 genomes and has MAF of 0.0012% gnomAD databases. The in silico prediction of the variant is disease causing by PolyPhen-2, SIFT, MutationTaster and CADD. In summary, the variant meets our criteria to be classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000668384	SCV005051872	pathogenic	Mucopolysaccharidosis, MPS-III-B	2024-02-01	criteria provided, single submitter	curation
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000668384	SCV000929907	uncertain significance	Mucopolysaccharidosis, MPS-III-B	2019-01-01	flagged submission	literature only	PM2:Very low frequency in ExAC. PP3:multiple lines of computational evidence supporting a deleterious effect (DANN, MutationTaster, GERP, SIFT)
PreventionGenetics, part of Exact Sciences	RCV004751657	SCV005347205	pathogenic	NAGLU-related disorder	2024-06-13	no assertion criteria provided	clinical testing	The NAGLU c.874G>A variant is predicted to result in the amino acid substitution p.Gly292Arg. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with mucopolysaccharidosis (see for example, Table 2, Bunge et al. 1999. PubMed ID: 9950362; Table 2, Tessitore et al. 2000. PubMed ID: 11153910; Table 1, Zanetti et al. 2019. PubMed ID: 30809705). An in vitro experimental study suggests this variant, in the compound heterozygous state, abolishes enzymatic activity (Table 5, Pollard et al. 2012. PubMed ID: 22976768). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.