Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000665218 | SCV000789296 | likely pathogenic | Mucopolysaccharidosis, MPS-III-A | 2017-01-26 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000665218 | SCV001339049 | pathogenic | Mucopolysaccharidosis, MPS-III-A | 2023-08-02 | criteria provided, single submitter | clinical testing | Variant summary: SGSH c.1167C>A (p.Asn389Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251050 control chromosomes (gnomAD). c.1167C>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A; e.g. Bunge_1997, Valstar_2010, Wijburg_2022). In addition, the variant has also been reported in heterozygous state in individuals with a clinical phenotype of neuronal ceroid lipofuscinosis (DiFruscio_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different missense affecting the same codon (p.Asn389Ser) is classified as pathogenic by our laboratory, indicating that this residue is clinically important. The following publications have been ascertained in the context of this evaluation (PMID: 9401012, 9744479, 11668611, 21061399, 24816101, 26075876, 25807448, 32036093). Four other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Invitae | RCV000665218 | SCV001419344 | pathogenic | Mucopolysaccharidosis, MPS-III-A | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 389 of the SGSH protein (p.Asn389Lys). This variant is present in population databases (rs764057581, gnomAD 0.004%). This missense change has been observed in individuals with mucopolysaccharidosis type III (PMID: 11903343, 21061399, 34991944). ClinVar contains an entry for this variant (Variation ID: 550465). 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 SGSH protein function. This variant disrupts the p.Asn389 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22976768). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ce |
RCV002275097 | SCV002563446 | pathogenic | not provided | 2023-11-01 | criteria provided, single submitter | clinical testing | SGSH: PM3:Very Strong, PM2, PM5, PP4 |
| Baylor Genetics | RCV000665218 | SCV004201090 | pathogenic | Mucopolysaccharidosis, MPS-III-A | 2023-09-19 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV000665218 | SCV002095117 | likely pathogenic | Mucopolysaccharidosis, MPS-III-A | 2020-06-18 | no assertion criteria provided | clinical testing |