Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
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 | 2023-12-02 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 545 of the HGSNAT protein (p.Thr545Lys). This variant is present in population databases (rs377050184, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with HGSNAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 427177). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HGSNAT protein function. 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. |