ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1447dup (p.Tyr483fs) (rs778021009)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674055 SCV000799328 likely pathogenic Mucopolysaccharidosis, MPS-III-B 2018-04-13 criteria provided, single submitter clinical testing
Invitae RCV001243748 SCV001416929 pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V 2020-08-07 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the NAGLU gene (p.Tyr483Leufs*33). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 229 amino acids of the NAGLU protein. This variant is present in population databases (rs778021009, ExAC 0.005%). This variant has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 9832037, 27590925). ClinVar contains an entry for this variant (Variation ID: 557862). This variant disrupts the C-terminus of the NAGLU protein. Other variant(s) that disrupt this region (p.Arg533*) have been determined to be pathogenic (PMID: 18218046). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000674055 SCV001448582 pathogenic Mucopolysaccharidosis, MPS-III-B 2020-11-06 criteria provided, single submitter clinical testing Variant summary: NAGLU c.1447dupT (p.Tyr483LeufsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.5e-06 in 222278 control chromosomes. c.1447dupT has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B; e.g. Beesley_1998, Truxal_2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence that cells expressing the variant had no detectable enzyme activity in-vitro (e.g. Clark_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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