ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1073C>T (p.Pro358Leu)

gnomAD frequency: 0.00004  dbSNP: rs368687817
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000778497 SCV000914765 uncertain significance Mucopolysaccharidosis, MPS-III-B 2018-11-16 criteria provided, single submitter clinical testing The NAGLU c.1073C>T (p.Pro358Leu) variant is a missense variant that has been reported in a homozygous state in two individuals with mucopolysaccharidosis type IIIB (MPS IIIB) (Schmidtchen et al. 1998; Pollard et al. 2013); however, one of these individuals was also homozygous for a second missense variant that has been previously reported in association with MPS III. Several family members of the double homozygote shared the same genotype, but whether these individuals were also affected is not reported. This variant is reported at a frequency of 0.000163 in the South Asian population of the Genome Aggregation Database. Assays of enzyme activity in transfected CHO cells and in fibroblasts from a homozygous patient showed little to no residual enzyme activity (Schmidtchen et al. 1998; Mauri et al. 2013), but an assay in transfected HEK293 cells suggested the variant enzyme retains ~40% residual activity (Clark et al. 2018). Based on the available evidence, the p.Pro358Leu variant is classified as of uncertain significance but suspicious for pathogenicity for mucopolysaccharidosis type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001305250 SCV001494579 uncertain significance Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V 2022-07-25 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001805845 SCV002050785 uncertain significance not specified 2021-12-06 criteria provided, single submitter clinical testing 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) 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 one publication reports experimental evidence evaluating an impact on protein function (Schmidtchen_1998). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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