This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 358 of the NAGLU protein (p.Pro358Leu). This variant is present in population databases (rs368687817, gnomAD 0.02%). This missense change has been observed in individual(s) with Sanfilippo syndrome type B (PMID: 9443878). ClinVar contains an entry for this variant (Variation ID: 631771). 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: 9443878, 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.

Variant summary: NAGLU c.1073C>T (p.Pro358Leu) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, tim-barrel domain (IPR024733) 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 3.3e-05 in 244814 control chromosomes. c.1073C>T has been reported in the literature as a homozygous genotype in the cell line derived from at-least one individual affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (Schmidtchen_1998, Vallejo-Diez_2018) and also as a homozygous genotype in cis with another variant, p.Tyr92His in another individual whose identity as a distinct occurrence cannot be confirmed (example, Pollard_2013). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (Schmidtchen_1998, Clark_2018). The most pronounced variant effect results in <10% of normal intracellular and secreted alpha-N-Acetylglucosaminidase enzyme activity as measured by stable transfection of Chinese hamster ovary cells, by cDNA mutagenized to correspond to the NAGLU missense mutations (Schmidtchen_1998). However, Clark_2018 reported this variant produced about 43% of WT activity in HEK293 cells. The following publications have been ascertained in the context of this evaluation (PMID: 29979746, 22976768, 9443878, 30408744). ClinVar contains an entry for this variant (Variation ID: 631771). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.