Submissions for variant NM_000046.5(ARSB):c.1299dup (p.Arg434Ter)

dbSNP: rs1355071930

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056740	SCV001221202	pathogenic	Mucopolysaccharidosis type 6	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg434*) in the ARSB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 100 amino acid(s) of the ARSB protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ARSB-related conditions. ClinVar contains an entry for this variant (Variation ID: 852181). This variant disrupts a region of the ARSB protein in which other variant(s) (p.Ser465*) have been determined to be pathogenic (PMID: 10036316, 17458871, 18486607). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001056740	SCV003922661	likely pathogenic	Mucopolysaccharidosis type 6	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: ARSB c.1299dupT (p.Arg434X) results in a premature termination codon and is predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Although the variant is not expected to cause absense of the protein through nonsense mediated decay, this variant is predicted to disrupt the last 100 amino acids in the protein sequence. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251424 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1299dupT in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001056740	SCV004206760	likely pathogenic	Mucopolysaccharidosis type 6	2023-10-03	criteria provided, single submitter	clinical testing