ClinVar Miner

Submissions for variant NM_000181.4(GUSB):c.1337G>A (p.Trp446Ter) (rs1434169374)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590006 SCV000695937 pathogenic Mucopolysaccharidosis type 6 2016-12-22 criteria provided, single submitter clinical testing Variant summary: The GUSB c.1337G>A (p.Trp446X) variant results in a premature termination codon, predicted to cause a truncated or absent GUSB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), but has been reported in an affected individual who was a compound heterozygote. The variant, c.1338G>A, which causes the same nonsense mutation has been reported, however, the variant is located in a duplicate of Gs, therefore, depending on nomenclature used, it could be the exact same variant and since both variants cause the same nonsense mutation. OMIM cites the c.1338G>A variant as "pathogenic." Therefore, due to the nature of the variant and the nonsense being observed in an affected individual which had very limited Beta-glucuronidase enzyme activity, the variant of interest has been classified as "pathogenic."
Invitae RCV001206155 SCV001377450 pathogenic Mucopolysaccharidosis type 7 2019-07-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp446*) in the GUSB gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with mucopolysaccharidosis type VII (MPS VII) (PMID: 9490302). ClinVar contains an entry for this variant (Variation ID: 495724). 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. Loss-of-function variants in GUSB are known to be pathogenic (PMID: 19224584). For these reasons, this variant has been classified as Pathogenic.

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