ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1772T>C (p.Leu591Pro)

gnomAD frequency: 0.00001  dbSNP: rs1215582852
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674403 SCV000799732 uncertain significance Mucopolysaccharidosis, MPS-III-B 2018-05-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193369 SCV001362137 uncertain significance not specified 2019-10-04 criteria provided, single submitter clinical testing Variant summary: NAGLU c.1772T>C (p.Leu591Pro) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, C-terminal 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 8.2e-06 in 242902 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1772T>C has been reported in the literature in a compound heterozygote individual affected with a severe form of Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B)(Beesley_1998). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001855608 SCV002116927 pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V 2023-11-08 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 591 of the NAGLU protein (p.Leu591Pro). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type IIIB (PMID: 9832037; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558175). 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%. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000674403 SCV002093280 uncertain significance Mucopolysaccharidosis, MPS-III-B 2020-02-03 no assertion criteria provided clinical testing

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