ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.2116C>T (p.Gln706Ter) (rs752527478)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668667 SCV000793305 likely pathogenic Mucopolysaccharidosis, MPS-III-B 2017-08-10 criteria provided, single submitter clinical testing
Invitae RCV001060496 SCV001225189 likely pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V 2019-01-15 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the NAGLU gene (p.Gln706*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acids of the NAGLU protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Sanfilippo syndrome type B (PMID: 9443875). ClinVar contains an entry for this variant (Variation ID: 553260). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668667 SCV001448365 pathogenic Mucopolysaccharidosis, MPS-III-B 2020-11-02 criteria provided, single submitter clinical testing Variant summary: NAGLU c.2116C>T (p.Gln706X) results in a premature termination codon in the last exon (exon 6) of the NAGLU gene and predicted to cause a truncation of the encoded protein. The variant allele was found at a frequency of 8e-06 in 251326 control chromosomes. c.2116C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) and subsequently cited by others (example, Zhao_1998, Whitley_2018, Schmidtchen_1998, Yogalingam_2001, Jain_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal NAGLU enzyme activity and elevated urine glycosaminoglycan (GAG) and cerebrospinal fluid heparan sulfate levels (example, Whitley_2018). 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 likely pathogenic citing at-least one overlapping publication utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

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