ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1277G>A (p.Gly426Asp)

gnomAD frequency: 0.00001  dbSNP: rs771151036
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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 RCV000796856 SCV000936387 pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V 2024-09-27 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 426 of the NAGLU protein (p.Gly426Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type III (internal data). 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: 643204). 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 RCV004526026 SCV005039988 uncertain significance not specified 2024-03-08 criteria provided, single submitter clinical testing Variant summary: NAGLU c.1277G>A (p.Gly426Asp) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, tim-barrel domain (IPR024733) 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 4e-06 in 250644 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1277G>A has been reported in the literature in one unspecified individual affected with Inherited metabolic disorders (Almeida_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35614200). ClinVar contains an entry for this variant (Variation ID: 643204). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV000796856 SCV005646078 likely pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V 2024-03-13 criteria provided, single submitter clinical testing

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