Submissions for variant NM_000046.5(ARSB):c.215T>G (p.Leu72Arg)

gnomAD frequency: 0.00001  dbSNP: rs397514441

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000677516	SCV000803026	likely pathogenic	Mucopolysaccharidosis type 6	2018-01-01	criteria provided, single submitter	curation	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); Reputable source identifies as pathogenic (PP5)
Invitae	RCV000677516	SCV000955328	pathogenic	Mucopolysaccharidosis type 6	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 72 of the ARSB protein (p.Leu72Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 16435196, 17458871, 25190157; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 559740). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSB protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000677516	SCV001370604	pathogenic	Mucopolysaccharidosis type 6	2020-05-07	criteria provided, single submitter	clinical testing	Variant summary: ARSB c.215T>G (p.Leu72Arg) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182450 control chromosomes. c.215T>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) with early onset and classical, rapidly progressing disease phenotype in the homozygotes (Petry_2005, Karageorgos_2007). These data indicate that the variant is very likely to be associated with disease. One of these publications also reported very low or undetectable ASB protein levels and undetectable enzymatic activities in skin fibroblasts derived from homozygous patients (Karageorgos_2007). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000677516	SCV002785020	likely pathogenic	Mucopolysaccharidosis type 6	2021-10-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000677516	SCV003817884	pathogenic	Mucopolysaccharidosis type 6	2022-03-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000677516	SCV004209214	pathogenic	Mucopolysaccharidosis type 6	2023-08-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000677516	SCV001457630	likely pathogenic	Mucopolysaccharidosis type 6	2020-09-16	no assertion criteria provided	clinical testing