ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.1336+2T>G

gnomAD frequency: 0.00003  dbSNP: rs768012515
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Total submissions: 5
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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 RCV000677476 SCV000802985 pathogenic Mucopolysaccharidosis type 6 2018-01-01 criteria provided, single submitter curation Splicing variant in canonical site (PVS1); In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in ExAC (PM2)
CeGaT Center for Human Genetics Tuebingen RCV000998401 SCV001154430 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000677476 SCV002244733 pathogenic Mucopolysaccharidosis type 6 2023-11-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the ARSB gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs768012515, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 14974081, 17458871, 24875751). ClinVar contains an entry for this variant (Variation ID: 559702). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000677476 SCV002511458 pathogenic Mucopolysaccharidosis type 6 2022-04-29 criteria provided, single submitter clinical testing Variant summary: ARSB c.1336+2T>G 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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251398 control chromosomes (gnomAD). c.1336+2T>G has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome), including two homozygotes (Karageorgos_2004, Karageorgos_2007, Chistiakov_2014). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000677476 SCV004206716 pathogenic Mucopolysaccharidosis type 6 2023-11-16 criteria provided, single submitter clinical testing

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