Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory of Diagnosis and Therapy of Lysosomal Disorders, |
RCV000790554 | SCV000929895 | uncertain significance | Mucopolysaccharidosis, MPS-III-A | 2019-01-01 | criteria provided, single submitter | literature only | PM2: Very low frequency in ExAc. PP3:multiple lines of computational evidence supporting a deleterious effect (DANN, MutationTaster, GERP, SIFT) |
| Invitae | RCV000790554 | SCV001578965 | pathogenic | Mucopolysaccharidosis, MPS-III-A | 2023-10-14 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 150 of the SGSH protein (p.Arg150Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 11182930, 30809705). ClinVar contains an entry for this variant (Variation ID: 638088). 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 SGSH protein function. This variant disrupts the p.Arg150 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9401012, 9554748, 9744479, 10727844, 11343308, 21061399, 21204211). 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. |
| Genome- |
RCV000790554 | SCV002045103 | likely pathogenic | Mucopolysaccharidosis, MPS-III-A | 2021-11-07 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000790554 | SCV002598580 | likely pathogenic | Mucopolysaccharidosis, MPS-III-A | 2022-09-29 | criteria provided, single submitter | clinical testing | Variant summary: SGSH c.448C>T (p.Arg150Trp) results in a non-conservative amino acid change located in the sulfatase, N-terminal domain (IPR000917) of 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 4e-06 in 250536 control chromosomes (gnomAD). c.448C>T has been reported in the literature as a biallelic genotype and in the heterozygous state in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (e.g. Beesley_2000, Chabas_2001, Zanetti_2019, Kong_2020, Wijburg_2022). These data indicate that the variant is likely to be associated with disease. Other variants affecting the same amino acid residue (p.Arg150Gln, p.Arg150Gly) have been cited in ClinVar and/or HGDM as pathogenic/likely pathogenic and disease-associated. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV000790554 | SCV004201069 | likely pathogenic | Mucopolysaccharidosis, MPS-III-A | 2023-10-23 | criteria provided, single submitter | clinical testing |