Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001378638 | SCV001576254 | likely pathogenic | Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 | 2024-01-31 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 482 of the HGSNAT protein (p.Met482Lys). This variant is present in population databases (rs121908284, gnomAD 0.007%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIC (PMID: 17033958). This variant is also known as c.1529T>A, p.M510K. ClinVar contains an entry for this variant (Variation ID: 1234). 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. Experimental studies have shown that this missense change affects HGSNAT 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323346 | SCV004029922 | likely pathogenic | Sanfilippo syndrome | 2023-07-12 | criteria provided, single submitter | clinical testing | Variant summary: HGSNAT c.1445T>A (p.Met482Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249234 control chromosomes (gnomAD). c.1445T>A has been reported in the literature in an individual affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (example: Hrebicek_HGSNAT_2006). Multiple publications have reported this variant impairs normal protein activity (examples: Feldhammer_2009 and Fedele_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20583299, 19823584, 17033958). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| OMIM | RCV000001293 | SCV000021443 | pathogenic | Mucopolysaccharidosis, MPS-III-C | 2006-11-01 | no assertion criteria provided | literature only |