Submissions for variant NM_000046.5(ARSB):c.971G>T (p.Gly324Val)

gnomAD frequency: 0.00004  dbSNP: rs398123125

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078005	SCV000109843	pathogenic	not provided	2014-01-07	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000677616	SCV000803134	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); Very low frequencyin GnomAD (PM2); Reputable source identifies as pathogenic (PP5)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000677616	SCV000835529	pathogenic	Mucopolysaccharidosis type 6	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 324 of the ARSB protein (p.Gly324Val). This variant is present in population databases (rs398123125, gnomAD 0.007%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17458871, 23557332; Invitae). ClinVar contains an entry for this variant (Variation ID: 92356). 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%. Studies have shown that this missense change alters ARSB gene expression (PMID: 23557332). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266364	SCV001444538	pathogenic	Inborn genetic diseases	2018-05-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000677616	SCV002809864	likely pathogenic	Mucopolysaccharidosis type 6	2021-11-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000677616	SCV004209125	likely pathogenic	Mucopolysaccharidosis type 6	2024-02-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000677616	SCV005203033	likely pathogenic	Mucopolysaccharidosis type 6	2024-07-22	criteria provided, single submitter	clinical testing	Variant summary: ARSB c.971G>T (p.Gly324Val) results in a non-conservative amino acid change in the Sulfatase, N-terminal domain 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 4e-06 in 251372 control chromosomes. c.971G>T has been reported in the literature in at-least one individual affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) 9Example: Ebbink_2016). 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 (Brands_2013). The following publications have been ascertained in the context of this evaluation (PMID: 26450354, 17458871, 33209960, 25654180, 23557332). ClinVar contains an entry for this variant (Variation ID: 92356). Based on the evidence outlined above, the variant was classified as likely pathogenic.