ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.691-1G>A

gnomAD frequency: 0.00001  dbSNP: rs778868348
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV000677584 SCV000803101 likely pathogenic Mucopolysaccharidosis type 6 2018-01-01 criteria provided, single submitter curation Splicing variant in canonical site (PVS1); Very low frequency in ExAC (PM2)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000677584 SCV003800732 likely pathogenic Mucopolysaccharidosis type 6 2024-01-25 criteria provided, single submitter clinical testing Variant summary: ARSB c.691-1G>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: Three predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251218 control chromosomes. c.691-1G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (e.g. Karageorgos_2007, Tomanin_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17458871, 30118150). ClinVar contains an entry for this variant (Variation ID: 559804). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000677584 SCV004293559 likely pathogenic Mucopolysaccharidosis type 6 2023-02-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the ARSB 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 ARSB are known to be pathogenic (PMID: 17458871, 22133300). This variant is present in population databases (rs778868348, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 24798265). This variant is also known as IVS3-1g>a. ClinVar contains an entry for this variant (Variation ID: 559804). Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (PMID: 17458871). 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.
Baylor Genetics RCV000677584 SCV005055526 pathogenic Mucopolysaccharidosis type 6 2024-02-21 criteria provided, single submitter clinical testing

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