Submissions for variant NM_000046.5(ARSB):c.1214-2A>G

dbSNP: rs1554069808

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000677467	SCV000802974	likely pathogenic	Mucopolysaccharidosis type 6	2018-01-01	criteria provided, single submitter	curation	Splicing variant in canonical site (PVS1); Absent from GnomAD (PM2)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000677467	SCV002556182	likely pathogenic	Mucopolysaccharidosis type 6	2022-06-27	criteria provided, single submitter	clinical testing	Variant summary: ARSB c.1214-2A>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 the canonical 3' splice acceptor site. Four predict the variant strengthens an alternate cryptic exonic 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251412 control chromosomes. c.1214-2A>G has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (example, Karageorgos_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.