Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000674664 | SCV000800043 | uncertain significance | Mucopolysaccharidosis, MPS-III-C | 2018-05-18 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001868282 | SCV002116716 | likely pathogenic | Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 | 2022-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 424 of the HGSNAT protein (p.Gly424Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. This variant disrupts the p.Gly424 amino acid residue in HGSNAT. Other variant(s) that disrupt this residue have been observed in individuals with HGSNAT-related conditions (PMID: 20825431), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects HGSNAT function (PMID: 19823584, 20583299). 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) performed at Invitae indicates that this missense variant is expected to disrupt HGSNAT protein function. ClinVar contains an entry for this variant (Variation ID: 558400). This variant is also known as p.G452S with gene alias TMEM76. This missense change has been observed in individual(s) with mucomucopolysaccharidosis type III and/or mucopolysaccharidosis type III (PMID: 17033958, 24767253). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002282322 | SCV002572009 | likely pathogenic | Sanfilippo syndrome | 2022-08-12 | criteria provided, single submitter | clinical testing | Variant summary: HGSNAT c.1270G>A (p.Gly424Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 241552 control chromosomes (gnomAD). c.1270G>A has been reported in the literature as a biallelic genotype in individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C; Hrebicek_2006, Fernandez-Marmiesse_2014). These data indicate that the variant may be associated with disease. Two independent experimental evaluations report that the variant causes misfolding of the protein and prevents normal glycosylation, which results in the protein being retained and degraded in the ER (Feldhammer_2009, Fedele_2010). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |