Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000255417 | SCV000322433 | pathogenic | not provided | 2021-10-12 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate the variant causes negligible heparan acetyl CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT) enzyme activity and caused misfolding of the HGSNAT protein and retention in the endoplasmic reticulum (Fedele et al. 2010; Feldhammer et al. 2009); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17033958, 19823584, 18024218, 19479962, 32770643, 31228227, 20583299) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000587936 | SCV000699952 | pathogenic | Sanfilippo syndrome | 2017-06-05 | criteria provided, single submitter | clinical testing | Variant summary: The HGSNAT c.1411G>A (p.Glu471Lys) variant causes the change of "an acidic residue for a basic one just inside the lysosomal luman (Feldhammer_2009)" involving the alteration of a conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant . This variant was found in 1/120760 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic HGSNAT variant (0.001). The variant was reported in the literature in MPS type IIIC patients both in the homozygous state and in the compound heterozygous state with other pathogenic variants. Additionally, the variant expressed in various cell model systems was shown to have significantly decreased enzyme activity, and to result in production of misfolded HGSNAT protein that is abnormally glycosylated and not targeted to the lysosome (Fedele_2010, Feldhammer_2009). One clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. |
| Fulgent Genetics, |
RCV000763185 | SCV000893785 | pathogenic | Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000763185 | SCV001207109 | pathogenic | Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 471 of the HGSNAT protein (p.Glu471Lys). This variant is present in population databases (rs753355844, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 17033958, 18024218, 19479962). This variant is also known as p.E499K. ClinVar contains an entry for this variant (Variation ID: 265483). 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: 20583299). For these reasons, this variant has been classified as Pathogenic. |
| Counsyl | RCV000665568 | SCV000789714 | likely pathogenic | Mucopolysaccharidosis, MPS-III-C | 2017-02-13 | no assertion criteria provided | clinical testing | |
| Natera, |
RCV000665568 | SCV001460471 | pathogenic | Mucopolysaccharidosis, MPS-III-C | 2020-09-16 | no assertion criteria provided | clinical testing |