ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1073C>T (p.Pro358Leu) (rs368687817)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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 2020-09-28 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 358 of the NAGLU protein (p.Pro358Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs368687817, ExAC 0.01%). This variant has been observed in individual(s) with Sanfilippo syndrome type B (PMID: 9443878). ClinVar contains an entry for this variant (Variation ID: 631771). Experimental studies have shown that this variant affects NAGLU protein 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.

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