This variant is interpreted as a Likely Pathogenic, for Mucopolysaccharidosis type VI, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:14974081).

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000549491). A different missense change at the same codon (p.Trp312Arg) has been reported to be associated with ARSB-related disorder (PMID: 17458871). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: ARSB c.936G>T (p.Trp312Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251338 control chromosomes. c.936G>T has been observed in individual(s) affected with Mucopolysaccharidosis Type VI (Karageorgos_2004). At least one publication reports experimental evidence evaluating an impact on protein function showing low levels of ARSB protein with very little activity (Karageorgos_2004). The following publication has been ascertained in the context of this evaluation (PMID: 14974081). ClinVar contains an entry for this variant (Variation ID: 549491). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 312 of the ARSB protein (p.Trp312Cys). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects ARSB function (PMID: 14974081). 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. ClinVar contains an entry for this variant (Variation ID: 549491). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 14974081).

The c.936G>T variant in ARSB is a missense variant predicted to cause substitution of tryptophan to cysteine at amino acid 312. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 14974081). Functional studies show that this variant may disrupt protein function (PMID: 14974081). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Likely Pathogenic.