ClinVar Genomic variation as it relates to human health

The SGSH c.734G>A (p.Arg245His) variant is one of the most commonly detected variants in individuals with mucopolysaccharidosis type III, accounting for up to 58% of disease alleles in some European populations (Fedele et al. 2015). Across a selection of the available literature, the p.Arg245His variant has been identified in a homozygous state in 37 individuals, in a compound heterozygous state in 75 individuals, and in a heterozygous state in two individuals (Blanch et al. 1997; Weber et al. 1998; Meyer et al. 2008; Valstar et al. 2010; Wilkin et al. 2016). The variant was absent from 20 control alleles but is reported at a frequency of 0.00060 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Arg245 residue is not conserved among human sulphatases. Functional studies showed that the p.Arg245His variant protein is expressed at a lower level than wild type, affects protein stability, and results in 83% of normal activity (Perkins et al. 1999; Sidhu et al. 2014). Based on the collective evidence, the p.Arg245His 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.

PS3, PS4, PP3

Published functional studies found R245H is associated with significantly reduced sulfamidase activity (Perkins et al., 1999); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18407553, 11182930, 25807448, 19383612, 21671382, 21061399, 10601282, 26331342, 9285796, 9158154, 24816101, 26787381, 27590925, 21228398, 31718697, 31980526, 32036093, 31589614, 12490062, 31031587, 33726816, 29023963)

The c.734G>A(p.Arg245His) missense variant in SGSH gene has been reported in individuals affected with mucopolysaccharidosis type IIIA (Wilkin et al., 2016). Experimental studies have shown that this missense change affects SGSH function (Perkins et al., 1999). This variant is reported with the allele frequency (0.03%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 245 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 245 of the SGSH protein (p.Arg245His). This variant is present in population databases (rs104894635, gnomAD 0.07%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIA (PMID: 9158154, 9700599, 15146460, 21061399, 22976768, 26331342). 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: 5107). 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 95%. Experimental studies have shown that this missense change affects SGSH function (PMID: 10601282). For these reasons, this variant has been classified as Pathogenic.

SGSH: PM3:Very Strong, PM2, PM5

Variant summary: The SGSH c.734G>A (p.Arg245His) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 30/72670 (1/2422), which does not exceed the estimated maximal expected allele frequency for a pathogenic SGSH variant of 1/309. The variant of interest has been reported in multiple affected individuals as homozygotes and compound heterozygotes via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.

PS3: Low/absent in vivo enzymatic activity in homozygote; Low in vitro enzymatic activity. PS4: The prevalence of the variant in affected individuals is significantly increase compared with the prevalence in controls. PM2: Absent from GnomAD

NM_000199.3(SGSH):c.734G>A(R245H) is classified as pathogenic in the context of mucopolysaccharidosis type IIIA. Sources cited for classification include the following: PMID 22976788, 21061399, 26787381 and 10601282. Classification of NM_000199.3(SGSH):c.734G>A(R245H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

The SGSH c.734G>A variant is predicted to result in the amino acid substitution p.Arg245His. This variant was documented to be pathogenic for Sanfilippo syndrome type A (Blanch et al. 1997. PubMed ID: 9158154; Nijmeijer et al. 2019. PubMed ID: 31718697; Ugrinov et al. 2015. PubMed ID: 25807448). At PreventionGenetics, we have also previously identified this variant in affected patients. This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.