ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.1297C>T (p.Arg433Trp)

gnomAD frequency: 0.00010  dbSNP: rs777267343
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665964 SCV000790185 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2017-03-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000665964 SCV000893480 pathogenic Mucopolysaccharidosis, MPS-III-A 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000665964 SCV000957485 pathogenic Mucopolysaccharidosis, MPS-III-A 2021-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 433 of the SGSH protein (p.Arg433Trp). This variant is present in population databases (rs777267343, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 11182930, 15542396, 29023963). ClinVar contains an entry for this variant (Variation ID: 551014). 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. Experimental studies have shown that this missense change affects SGSH function (PMID: 15542396). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000665964 SCV001361816 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-07-05 criteria provided, single submitter clinical testing Variant summary: SGSH c.1297C>T (p.Arg433Trp) results in a non-conservative amino acid change located in a domain of unknown function, DUF4976 (IPR032506) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250408 control chromosomes (gnomAD). The variant, c.1297C>T, has been reported in the literature in homozygosity or in compound heterozygous state in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (e.g. Beesley_2000, Chabas_2001, Heron_2011, Pollard_2013). These data indicate that the variant is very likely to be associated with disease. Publications reported no significant sulfamidase activity in fibroblasts from a homozygous patient (Montfort_2004), and in transiently transfected mammalian cells (Muschol_2004). Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic (1x) and pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000665964 SCV002045483 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2021-11-07 criteria provided, single submitter clinical testing

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