Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory of Diagnosis and Therapy of Lysosomal Disorders, |
RCV000677609 | SCV000803126 | likely pathogenic | Mucopolysaccharidosis type 6 | 2018-01-01 | criteria provided, single submitter | curation | In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in ExAC (PM2); Multiple lines of computational evidence support a deleterious effect on the gene product (PP3); Reputable source identifies as pathogenic (PP5) |
| Labcorp Genetics |
RCV000677609 | SCV001586724 | pathogenic | Mucopolysaccharidosis type 6 | 2023-06-21 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 313 of the ARSB protein (p.Pro313Ala). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ARSB function (PMID: 27826022). 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 ARSB protein function. ClinVar contains an entry for this variant (Variation ID: 559826). This missense change has been observed in individual(s) with mucolipidosis VI (PMID: 17458871, 17643332, 23557332). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000677609 | SCV002819806 | pathogenic | Mucopolysaccharidosis type 6 | 2022-12-25 | criteria provided, single submitter | clinical testing | Variant summary: ARSB c.937C>G (p.Pro313Ala) 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 251338 control chromosomes. c.937C>G has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with clinically and biochemically characterized Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (example, PMID: 23557332, 26450354, 25654180, 17643332, 30083803, 28552677, 27826022). These data indicate that the variant is very likely to be associated with disease. No direct experimental evidence demonstrating an impact on protein function has been ascertained in this assessment, although at-least one study describes its identification in two homozygous individuals with measurement of enzyme deficiency in leukocytes or fibroblasts confirming a diagnosis of MPS VI (PMID: 30083803). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Natera, |
RCV000677609 | SCV002084976 | pathogenic | Mucopolysaccharidosis type 6 | 2020-10-21 | no assertion criteria provided | clinical testing |