Submissions for variant NM_000046.5(ARSB):c.1213+6T>C

dbSNP: rs1554074118

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000677466	SCV000802973	pathogenic	Mucopolysaccharidosis type 6	2018-01-01	criteria provided, single submitter	curation	Splicing variant in NON-canonical site (PVS1); in vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Absent from GnomAD (PM2);
Invitae	RCV000677466	SCV001514925	pathogenic	Mucopolysaccharidosis type 6	2023-09-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 559692). This variant has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 30809705; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 6 of the ARSB gene. It does not directly change the encoded amino acid sequence of the ARSB protein. It affects a nucleotide within the consensus splice site.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000677466	SCV004030090	likely pathogenic	Mucopolysaccharidosis type 6	2023-07-07	criteria provided, single submitter	clinical testing	Variant summary: ARSB c.1213+6T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the 5' splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251358 control chromosomes. c.1213+6T>C has been reported in the literature in at least one compound heterozygous and one homozygous individual affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (examples: DiNatale_2008, Ferla_2015, Zanetti_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in a homozygous individual (Zanetti_2019).The following publications have been ascertained in the context of this evaluation (PMID: 22971959, 17672828, 25654180, 30809705). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.