Submissions for variant NM_000263.4(NAGLU):c.1562C>T (p.Pro521Leu)

gnomAD frequency: 0.00002  dbSNP: rs104894595

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001043674	SCV001207432	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 521 of the NAGLU protein (p.Pro521Leu). This variant is present in population databases (rs104894595, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 9443875, 20852935, 28306536). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1566). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001632	SCV001362135	pathogenic	Mucopolysaccharidosis, MPS-III-B	2019-02-13	criteria provided, single submitter	clinical testing	Variant summary: NAGLU c.1562C>T (p.Pro521Leu) results in a non-conservative amino acid change located in the C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 271726 control chromosomes (gnomAD). c.1562C>T has been reported in the literature in compound heterozygous and homozygous individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (e.g. Zhao 1998, Beesley 2005, Valstar 2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001043674	SCV002813368	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2024-05-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001729332	SCV003816285	likely pathogenic	not provided	2022-03-02	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000001632	SCV005045188	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2024-02-08	criteria provided, single submitter	clinical testing	The NAGLU c.1562C>T (p.Pro521Leu) variant has been reported in 13 individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) and is reported to segregate with disease in nine individuals in two families (Beesley CE et al., PMID: 9832037; Valstar MJ et al., PMID: 20852935; Weber B et al., PMID: 10094189; Zhao HG et al., PMID: 9443875; Zheng Q et al., PMID: 28306536). Of those individuals, nine were compound heterozygous for the variant and a pathogenic/likely pathogenic variant was confirmed to be in trans (Valstar MJ et al., PMID: 20852935; Zhao HG et al., PMID: 9443875) and two individuals were homozygous for the variant (Beesley CE et al., PMID: 9832037; Weber B et al., PMID: 10094189). This variant is only observed on 7 out of 277,290 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to NAGLU function. This variant has been reported in the ClinVar database as a pathogenic or likely pathogenic germline variant by seven submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000001632	SCV005415787	pathogenic	Mucopolysaccharidosis, MPS-III-B		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PP4+PP3_Moderate
OMIM	RCV000001632	SCV000021788	pathogenic	Mucopolysaccharidosis, MPS-III-B	1999-01-01	no assertion criteria provided	literature only
SingHealth Duke-NUS Institute of Precision Medicine	RCV000001632	SCV000853170	uncertain significance	Mucopolysaccharidosis, MPS-III-B	2017-06-07	no assertion criteria provided	curation
GeneReviews	RCV001030807	SCV001194296	not provided	Mucopolysaccharidosis		no assertion provided	literature only
Clinical Genetics, Academic Medical Center	RCV001729332	SCV001978741	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001729332	SCV001980317	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000001632	SCV002093272	pathogenic	Mucopolysaccharidosis, MPS-III-B	2020-08-25	no assertion criteria provided	clinical testing