ClinVar Genomic variation as it relates to human health

Variant summary: The SGSH c.892T>C (p.Ser298Pro) variant involves the alteration of a conserved nucleotide that lies within the Alkaline-phosphatase-like, core domain, Sulfatase, N-terminal domain, and Alkaline phosphatase-like, alpha/beta/alpha domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies found no to minimal (2.3% of wild-type) heparin-N sulfatase activity associated with this variant (Pollard_JIMD_2013, Muschol_AJMG_2011). This variant was found in the large control database ExAC and in the literature at a frequency of 0.0000917 (11/120004 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic SGSH variant (0.0032275). The variant has been found in numerous MPS IIIA patients, in compound heterozygotes as well as homozygotes, and was reported as being associated with a clinically mild phenotype (Valstar_Mutat_Annals of Neurology_2010, Meyer_HM_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

This variant has been previously reported as disease-causing PMIDs 21671382, 29023963, 9401012, 24816101, 25807448.

Published functional studies demonstrate an effect on folding and stability of the sulfamidase enzyme, resulting in significantly reduced enzymatic activity (Muschol et al., 2011) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function This variant is associated with the following publications: (PMID: 31980526, 31536183, 32581362, 31718697, 29023963, 28451919, 24524415, 21204211, 24271936, 21061399, 15146460, 22976768, 24816101, 26787381, 18407553, 25807448, 9401012, 21671382)

PS3, PM2, PM3_Very Strong

This variant has been previously reported as a homozygous variant or a heterozygous variant in combination with another pathogenic variant in SGSH in several individuals with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (PMID: 9401012, 18407553, 21671382, 22976768, 29023963). Functional studies have demonstrated that this variant affects the folding and stability of the SGSH protein, resulting in reduced enzymatic activity (PMID: 21671382). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.011% (30/282024) and thus is presumed to be rare. The c.892T>C (p.Ser298Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.892T>C (p.Ser298Pro) variant is classified as Pathogenic.

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 298 of the SGSH protein (p.Ser298Pro). This variant is present in population databases (rs138504221, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIA (PMID: 9401012, 18407553, 21671382, 22976768, 29023963). ClinVar contains an entry for this variant (Variation ID: 30459). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SGSH protein function. Experimental studies have shown that this missense change affects SGSH function (PMID: 21671382). For these reasons, this variant has been classified as Pathogenic.

The SGSH c.892T>C (p.Ser298Pro) variant has been reported in four studies and is found in a total of 51 individuals with mucopolysaccharidosis, type III including four in a homozygous state, 45 in a compound heterozygous state, and two in a heterozygous state in whom a second variant was not identified (Bunge et al. 1997; Meyer et al. 2008; Valstar et al. 2010; Shapiro et al. 2016). Individuals carrying the p.Ser298Pro variant demonstrate a milder phenotype (Meyer et al. 2008; Valstar et al. 2010). The p.Ser298Pro variant was absent from 100 controls but is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in BHK cells transfected with the p.Ser298Pro variant demonstrated the variant results in reduced protein stability compared to wild type as well as low residual sulfamidase activity (Muschol et al. 2011). Based on the collective evidence, the p.Ser298Pro variant is classified as pathogenic for mucopolysaccharidosis, type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.