ClinVar Genomic variation as it relates to human health

Variant summary: SGSH c.449G>A (p.Arg150Gln) results in a conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 276994 control chromosomes (gnomAD and publication data). c.449G>A has been reported in the literature as a homozygous and compound heterozygous allele in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Bunge 1997, Di Natale 1998, Heron 2010, Valstar 2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on enzyme activity, showing that the variant results in <10% of normal activity (Esposito 2000). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 150 of the SGSH protein (p.Arg150Gln). This variant is present in population databases (rs104894638, gnomAD 0.005%). This missense change has been observed in individuals with mucopolysaccharidosis type III (PMID: 9401012, 9554748, 9744479, 11343308, 21061399, 21204211). ClinVar contains an entry for this variant (Variation ID: 5113). 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 SGSH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SGSH function (PMID: 10727844). This variant disrupts the p.Arg150 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 11182930, 21204211), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

The SGSH c.449G>A variant is predicted to result in the amino acid substitution p.Arg150Gln. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with mucopolysaccharidosis type IIIA (see for example, Bunge et al. 1997. PubMed ID: 9401012; Yogalingam and Hopwood. 2001. PubMed ID: 11668611; Valstar et al. 2010. PubMed ID: 21061399). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. An in vitro experimental study suggests this variant abolishes enzyme activity (Esposito et al. 2000. PubMed ID: 10727844). Alternate missense substitutions affecting the same amino acid (p.Arg150Trp and p.Arg150Gly) have been reported in multiple individuals with mucopolysaccharidosis type IIIA (Beesley et al. 2000. PubMed ID: 11182930; Table S2, Héron et al. 2011. PubMed ID: 21204211). Given the evidence, the c.449G>A (p.Arg150Gln) variant is interpreted as pathogenic.