Submissions for variant NM_000263.4(NAGLU):c.2021G>A (p.Arg674His)

gnomAD frequency: 0.00003  dbSNP: rs104894590

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078455	SCV000110311	pathogenic	not provided	2013-11-12	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000001626	SCV000744579	pathogenic	Mucopolysaccharidosis, MPS-III-B	2015-09-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000001626	SCV000793107	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-07-27	criteria provided, single submitter	clinical testing
Invitae	RCV000817080	SCV000957620	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 674 of the NAGLU protein (p.Arg674His). This variant is present in population databases (rs104894590, gnomAD 0.003%). This missense change has been observed in individual(s) with MPS IIIB (PMID: 8650226, 9443875, 9950362, 20852935). ClinVar contains an entry for this variant (Variation ID: 1560). 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%. Experimental studies have shown that this missense change affects NAGLU function (PMID: 9443878). This variant disrupts the p.Arg674 amino acid residue in NAGLU. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9443875, 10094189). 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	RCV000001626	SCV000021782	pathogenic	Mucopolysaccharidosis, MPS-III-B	1996-06-11	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000001626	SCV000733580	pathogenic	Mucopolysaccharidosis, MPS-III-B		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000001626	SCV001463396	pathogenic	Mucopolysaccharidosis, MPS-III-B	2020-09-16	no assertion criteria provided	clinical testing