ClinVar Genomic variation as it relates to human health

Variant summary: NAGLU c.1694G>T (p.Arg565Leu) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, C-terminal (IPR024732) 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 1.2e-05 in 248730 control chromosomes. c.1694G>T has been reported in the literature in multiple individuals from one family affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) and has been subsequently cited by others (example, Al-Jasmi_2013, Kadali_2019). Moreover, other missense variants located at the same codon (p.Arg565Gln, p.Arg565Trp and p.Arg565Pro) have been reported in patients with Sanfilippo Syndrome B suggesting the critical relevance of Arginine 565 residue to protein function. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

A homozygous missense variant in exon 6 of the NAGLU gene that results in the amino acid substitution of Leucine for Arginine at codon 565 was detected. The observed variant c.1694G>T (p.Arg565Leu) has not been reported in the 1000 genomes and has a MAF of 0.0012% in the gnomAD database. The in-silico prediction of the variant are damaging by PolyPhen-2 (HumDiv), SIFT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 565 of the NAGLU protein (p.Arg565Leu). This variant is present in population databases (rs104894598, gnomAD 0.007%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 23430803). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 557013). 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. This variant disrupts the p.Arg565 amino acid residue in NAGLU. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10094189, 15933803). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.