ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1487T>C (p.Leu496Pro)

gnomAD frequency: 0.00001  dbSNP: rs569519789
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000592453 SCV000702005 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000652882 SCV000774754 uncertain significance Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V 2021-11-02 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 496 of the NAGLU protein (p.Leu496Pro). This variant is present in population databases (rs569519789, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with NAGLU-related conditions. ClinVar contains an entry for this variant (Variation ID: 497482). 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. Experimental studies have shown that this missense change affects NAGLU function (PMID: 29979746). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001829637 SCV003928889 pathogenic Mucopolysaccharidosis, MPS-III-B 2023-04-18 criteria provided, single submitter clinical testing Variant summary: NAGLU c.1487T>C (p.Leu496Pro) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 230624 control chromosomes. c.1487T>C has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B, Montenegro_2022). 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 and showed that this variant resulted in decreased enzyme activity (Clark_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV001829637 SCV002093269 uncertain significance Mucopolysaccharidosis, MPS-III-B 2020-09-04 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.