ClinVar Miner

Submissions for variant NM_152419.3(HGSNAT):c.1237C>T (p.Pro413Ser) (rs201346206)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000346177 SCV000474013 uncertain significance Sanfilippo syndrome 2016-06-14 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196774 SCV001367407 uncertain significance Retinitis pigmentosa 73 2018-10-15 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
Invitae RCV001240733 SCV001413703 uncertain significance Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 413 of the HGSNAT protein (p.Pro413Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs201346206, ExAC 0.06%). This variant has not been reported in the literature in individuals with HGSNAT-related disease. ClinVar contains an entry for this variant (Variation ID: 363147). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Genetics laboratory, University of Goettingen RCV001256203 SCV001429654 likely pathogenic Mucopolysaccharidosis, MPS-III-C 2020-08-14 criteria provided, single submitter clinical testing The HGSNAT variant c.1237C>T (p.(Pro413Ser)) is found at a population frequency of 0.03% in the gnomAD database, it affects a highly conserved nucleotide and a highly conserved amino acid and there is a moderate physicochemical difference between Pro and Ser. The variant has a pathogenic computational verdict based on 8 pathogenic predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, M-CAP, MutationTaster, PolyPhen-2 and SIFT vs 2 benign predictions from MVP and REVEL. This variant was found in trans with the known pathogenic HGSNAT mutation c.1622C>T (p.(Ser541Leu); ClinVar Variation ID: 569073) and the phenotype of our patient matched the phenotype typical for Mucopolysaccharidosis type IIIC (Sanfilippo C) patients. Thus, we consider this variant to be likely pathogenic. ACMG criteria used for classification: PM2, PM3, PP2, PP3.

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