ClinVar Miner

Submissions for variant NM_152419.3(HGSNAT):c.1634C>A (p.Thr545Lys) (rs377050184)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489607 SCV000577815 likely pathogenic not provided 2015-04-28 criteria provided, single submitter clinical testing The T545K variant in the HGSNAT gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The T545K variant was not observed in approximately 6100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T545K 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, in the helical transmembrane domain, that is conserved across species. Although, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function, missense variants in nearby residues (S539C and S541L) have been reported in the Human Gene Mutation Database in association with mucopolysaccharidosis IIIC (Stenson et al., 2014), supporting the functional importance of this region of the protein. The T545K variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV001359580 SCV001555455 uncertain significance Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2020-01-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 545 of the HGSNAT protein (p.Thr545Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is present in population databases (rs377050184, ExAC 0.002%). This variant has not been reported in the literature in individuals with HGSNAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 427177). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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. 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.

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