ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1660C>T (p.Pro554Ser)

gnomAD frequency: 0.00001  dbSNP: rs1049965915
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001917729 SCV002169636 uncertain significance Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 554 of the NAGLU protein (p.Pro554Ser). This variant is not present in population databases (gnomAD no frequency). 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: 1399524). 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%. 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 RCV004782818 SCV005395649 uncertain significance not specified 2024-09-05 criteria provided, single submitter clinical testing Variant summary: NAGLU c.1660C>T (p.Pro554Ser) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, C-terminal domain (IPR024732) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248144 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1660C>T in individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1399524). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV004955770 SCV005458752 uncertain significance Inborn genetic diseases 2024-12-03 criteria provided, single submitter clinical testing The c.1660C>T (p.P554S) alteration is located in exon 6 (coding exon 6) of the NAGLU gene. This alteration results from a C to T substitution at nucleotide position 1660, causing the proline (P) at amino acid position 554 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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