Submissions for variant NM_000263.4(NAGLU):c.1694G>C (p.Arg565Pro)

dbSNP: rs104894598

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000001634	SCV000267414	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2016-03-18	criteria provided, single submitter	reference population
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001634	SCV001362136	pathogenic	Mucopolysaccharidosis, MPS-III-B	2019-08-18	criteria provided, single submitter	clinical testing	Variant summary: NAGLU c.1694G>C (p.Arg565Pro) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, C-terminal domain (IPR024732) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248730 control chromosomes. c.1694G>C has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (Weber_1999, Chinen_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in homozygous individuals (Chinen_2005). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic citing only Weber_1999. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion	RCV000001634	SCV002012319	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: VCV000001568.3, PMID: 15933803, PS1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed in trans with a pathogenic variant (NM_000263.3:c.1444C>T) as compound heterozygous (3billion dataset, PM3). A different missense change at the same codon (p.Arg565Leu, p.Arg565Trp, p.Arg565Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000557013.3, VCV000001567.9 and VCV000030795.11, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.989, 3Cnet: 0.976, 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.
Invitae	RCV001851558	SCV002237157	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2023-07-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 565 of the NAGLU protein (p.Arg565Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 10094189, 15933803). ClinVar contains an entry for this variant (Variation ID: 1568). 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. 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, 23380547, 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.
OMIM	RCV000001634	SCV000021790	pathogenic	Mucopolysaccharidosis, MPS-III-B	2005-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000001634	SCV002093277	pathogenic	Mucopolysaccharidosis, MPS-III-B	2021-07-26	no assertion criteria provided	clinical testing