ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1211G>A (p.Trp404Ter) (rs904672363)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666363 SCV000790642 pathogenic Mucopolysaccharidosis, MPS-III-B 2017-04-04 criteria provided, single submitter clinical testing
Invitae RCV001043279 SCV001207006 pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V 2019-07-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the NAGLU gene (p.Trp404*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 340 amino acids of the NAGLU protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with mucopolysaccharidosis type IIIB (PMID: 9950362, 10094189, 24314109). ClinVar contains an entry for this variant (Variation ID: 551331). This variant disrupts the C-terminus of the NAGLU protein. Other variant(s) that disrupt this region (p.Arg626*) have been determined to be pathogenic (PMID: 8650226, 9832037, 10094189). 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.
Integrated Genetics/Laboratory Corporation of America RCV000666363 SCV001370578 pathogenic Mucopolysaccharidosis, MPS-III-B 2020-05-25 criteria provided, single submitter clinical testing Variant summary: NAGLU c.1211G>A (p.Trp404X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251350 control chromosomes. c.1211G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (example, Bunge_1999, Weber_1999, Delgadillo_2013, Whitley_2018). 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. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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