ClinVar Miner

Submissions for variant NM_000181.4(GUSB):c.1244+1G>A

gnomAD frequency: 0.00002  dbSNP: rs765969571
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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 RCV001251384 SCV001426967 pathogenic Mucopolysaccharidosis type 7 2020-07-10 criteria provided, single submitter clinical testing Variant summary: GUSB c.1244+1G>A 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 5 splicing donor site. These predictions are supported by at least one publication (Vervoort_1997) which demonstrated that the variant resulted in skipping of exon 6 and 7 with or without skipping of exon 9. The variant allele was found at a frequency of 8e-06 in 251272 control chromosomes (gnomAD). c.1244+1G>A has been reported in the literature in at least one individual (homozygous) affected with Mucopolysaccharidosis Type VII (Sly Syndrome) (Vervoort_1997). These data indicate that the variant may be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001251384 SCV002135488 pathogenic Mucopolysaccharidosis type 7 2023-10-16 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 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 present in population databases (rs765969571, gnomAD 0.009%). Disruption of this splice site has been observed in individual(s) with clinical features of mucopolysaccharidosis type VII and/or fetal hydrops (PMID: 9099834, 19224584). ClinVar contains an entry for this variant (Variation ID: 975000). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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