Submissions for variant NM_000263.4(NAGLU):c.1444C>T (p.Arg482Trp)

gnomAD frequency: 0.00001  dbSNP: rs104894596

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000001637	SCV000746455	pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-12-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000001637	SCV000788455	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2018-02-15	criteria provided, single submitter	clinical testing
Invitae	RCV001214384	SCV001386063	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 482 of the NAGLU protein (p.Arg482Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with MPS IIIB (PMID: 9950362, 12202988, 16151907, 16447797, 23667853, 28018442). ClinVar contains an entry for this variant (Variation ID: 1571). 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 NAGLU protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000001637	SCV002012317	pathogenic	Mucopolysaccharidosis, MPS-III-B	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence (ClinVar ID: VCV000001571.4, PS1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000027, PM2). The variant was observed in trans with a pathogenic variant (NM_000263.3:c.1694G>C) as compound heterozygous (3billion dataset, PM3). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.9, 3Cnet: 0.971, PP3). Patient's phenotype is considered compatible with Mucopolysaccharidosis type IIIB (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000001637	SCV004175844	pathogenic	Mucopolysaccharidosis, MPS-III-B	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.1444C>T(p.Arg482Trp) variant in NAGLU gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with Mucopolysaccharidosis IIIB (Kim JH, et. al., 2016; Tanaka A, et. al.,2002). The p.Arg482Trp variant has been reported with allele frequency of 0.003% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg482Trp in NAGLU is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 482 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified Pathogenic.
OMIM	RCV000001637	SCV000021793	pathogenic	Mucopolysaccharidosis, MPS-III-B	2002-01-01	no assertion criteria provided	literature only
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000001637	SCV002062062	pathogenic	Mucopolysaccharidosis, MPS-III-B		no assertion criteria provided	clinical testing