Submissions for variant NM_000263.4(NAGLU):c.1693C>T (p.Arg565Trp)

gnomAD frequency: 0.00010  dbSNP: rs104894597

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000001633	SCV000402914	pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-04-27	criteria provided, single submitter	clinical testing	The NAGLU c.1693C>T (p.Arg565Trp) variant has been reported to account for 3.4% of variant alleles in individuals with mucopolysaccharidosis type III and is associated with an attenuated phenotype (Yogalingham et al. 2001). The p.Arg565Trp variant has been reported in ten studies and is found in a total of 17 individuals including in four individuals in a homozygous state, in 11 individuals (including three sibling pairs) in a compound heterozygous state, and in two individuals in a heterozygous state (Beesley et al. 1998; Weber et al. 1999; Col et al. 2001; Tanaka et al. 2002; Lee-Chen et al. 2002; Beesley et al. 2005; Mangas et al. 2008; Valstar et al. 2010; Tang et al. 2013; Shi et al. 2014). The p.Arg565Trp variant was absent from 474 ethnically matched control chromosomes and is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. The p.Arg565Trp variant showed a drastic reduction in NAGLU enzyme activity despite normal mRNA levels in four studies (Lee-Chen et al. 2002; Mangas et al. 2008; Tang et al. 2013; Shi et al. 2014). Structural modelling showed that the p.Arg565Trp variant is located at the alpha-helical domain next to the enzyme binding site (Shi et al. 2014). Based on the collective evidence, the p.Arg565Trp variant is classified as pathogenic for mucopolysaccharidosis type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001633	SCV000919839	pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-10-02	criteria provided, single submitter	clinical testing	Variant summary: The NAGLU c.1693C>T (p.Arg565Trp) variant located in the Alpha-N-acetylglucosaminidase, C-terminal domain (IPR024732) (InterPro) causes a missense change involving a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional enzymatic studies showed very low to no alpha-N-acetyl-glucosaminidase activity in peripheral leukocytes and cultured fibroblasts of homozygotes and compound heterozygotes (Tanaka_2002 and Shi_2014). The variant was found in 10/274834 control chromosomes (gnomAD) at a frequency of 0.0000364, which does not exceed the estimated maximal expected allele frequency of a pathogenic NAGLU variant (0.0025). This variant was reported in multiple patients diagnosed with Sanfilippo syndrome (mucopolysaccharidosis IIIB), associated with a severe phenotype (Beesley_2005, Weber_Genet_1999, Shi_2014). In addition, a clinical diagnostic laboratory and a reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000001633	SCV001140449	pathogenic	Mucopolysaccharidosis, MPS-III-B	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001223228	SCV001395367	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2023-12-09	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 565 of the NAGLU protein (p.Arg565Trp). This variant is present in population databases (rs104894597, gnomAD 0.04%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 9832037, 12202988, 25466957). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1567). 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 95%. This variant disrupts the p.Arg565 amino acid residue in NAGLU. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9950362, 20852935, 28751108). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002269255	SCV002552800	pathogenic	not provided	2022-07-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23380547, 20852935, 18218046, 25466957, 9832037, 11668611, 10094189, 11286389, 29979746, 34440436, 31589614, 32014045)
Fulgent Genetics, Fulgent Genetics	RCV001223228	SCV002809439	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2021-11-01	criteria provided, single submitter	clinical testing
OMIM	RCV000001633	SCV000021789	pathogenic	Mucopolysaccharidosis, MPS-III-B	1999-01-01	no assertion criteria provided	literature only
Counsyl	RCV000001633	SCV000790179	pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-03-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000001633	SCV001463390	pathogenic	Mucopolysaccharidosis, MPS-III-B	2020-09-16	no assertion criteria provided	clinical testing