ClinVar Miner

Submissions for variant NM_152419.3(HGSNAT):c.848C>T (p.Pro283Leu) (rs121908282)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000512873 SCV000609302 likely pathogenic not provided 2017-03-01 criteria provided, single submitter clinical testing
GeneDx RCV000512873 SCV000617696 likely pathogenic not provided 2017-09-26 criteria provided, single submitter clinical testing The P283L variant in the HGSNAT gene has been reported previously, using alternate nomenclature P311L, in association with mucopolysaccharidosis IIIC, in an affected individual who was homozygous for the P283L variant, and in an affected individual who was heterozygous for the P283L variant and another HGSNAT variant (Hrebicek et al., 2006). The P283L variant is observed in 3/18754 (0.016%) alleles from individuals of East Asian background, in the ExAC dataset (Lek et al., 2016). The P283L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies show that P283L has reduced enzyme activity compared to wild type and mislocalization due to incorrect protein folding (Feldhammer et al., 2009; Fedele et al., 2010). We interpret P283L as a likely pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000763184 SCV000893784 likely pathogenic Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000763184 SCV000957002 likely pathogenic Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2018-08-14 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 283 of the HGSNAT protein (p.Pro283Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs121908282, ExAC 0.03%). This variant has been observed in individuals affected with Mucopolysaccharidosis IIIC (Sanfilippo C Syndrome) (PMID: 17033958). This variant is also known as P311L in the literature. ClinVar contains an entry for this variant (Variation ID: 1232). Experimental studies have shown that this missense change disrupts normal HGSNAT protein function (PMID: 19823584, 20583299). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000001291 SCV000021441 pathogenic Mucopolysaccharidosis, MPS-III-C 2006-11-01 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504894 SCV000599073 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research

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