ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.1166A>G (p.Asn389Ser) (rs1555620214)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664949 SCV000788991 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2016-12-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000664949 SCV000920204 pathogenic Mucopolysaccharidosis, MPS-III-A 2018-08-20 criteria provided, single submitter clinical testing Variant summary: SGSH c.1166A>G (p.Asn389Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. In silico studies also predicted damaging effect for the variant on enzyme structure or activity (Sidhu 2014, Ugrinov 2015). The variant was absent in 246048 control chromosomes (gnomAD). c.1166A>G has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Pollard 2013, Shapiro 2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000664949 SCV001578963 pathogenic Mucopolysaccharidosis, MPS-III-A 2020-09-16 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 389 of the SGSH protein (p.Asn389Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 22976768, 26787381). ClinVar contains an entry for this variant (Variation ID: 550252). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Asn389 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21061399,11903343). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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