ClinVar Miner

Submissions for variant NM_000181.4(GUSB):c.724+1G>T

dbSNP: rs2116026958
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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 RCV003226648 SCV003922562 likely pathogenic Mucopolysaccharidosis type 7 2023-03-14 criteria provided, single submitter clinical testing Variant summary: GUSB c.724+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251058 control chromosomes. To our knowledge, no occurrence of c.724+1G>T in individuals affected with Mucopolysaccharidosis Type VII (Sly Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003226648 SCV004627864 likely pathogenic Mucopolysaccharidosis type 7 2024-01-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the GUSB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GUSB are known to be pathogenic (PMID: 19224584). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GUSB-related conditions. ClinVar contains an entry for this variant (Variation ID: 2501051). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

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