Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| EGL Genetic Diagnostics, |
RCV000723435 | SCV000231992 | pathogenic | not provided | 2015-02-12 | criteria provided, single submitter | clinical testing | |
| Laboratory of Diagnosis and Therapy of Lysosomal Disorders, |
RCV000179701 | SCV000802975 | uncertain significance | Mucopolysaccharidosis type 6 | 2018-01-01 | criteria provided, single submitter | curation | Absent from GnomAD (PM2) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000779751 | SCV000916526 | pathogenic | Metachromatic leukodystrophy | 2018-05-24 | criteria provided, single submitter | clinical testing | Variant summary: ARSB c.1214G>A (p.Cys405Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Though the variant is located at an exon-intron junction, 5/5 computational tools predict no significant impact on normal splicing. These predictions have been confirmed by functional studies, where full-length mRNA containing the mutation c.1214G>A was detected (Jin 1992, Karageorgos 2007), predicted to result in a protein with the missense change p.C405Y. Three 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 246184 control chromosomes. This frequency is lower than expected for a pathogenic variant in ARSB causing Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (2e-05 vs 0.0022), allowing no conclusion about variant significance. The variant, c.1214G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) presenting with a slowly progressing, milder disease phenotype (Jin 1992, Karageorgos 2007). These data indicate that the variant is likely to be associated with disease. These publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Jin 1992, Karageorgos 2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Invitae | RCV000179701 | SCV001583438 | pathogenic | Mucopolysaccharidosis type 6 | 2020-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine with tyrosine at codon 405 of the ARSB protein (p.Cys405Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs118203941, ExAC 0.001%). This variant has been observed in individual(s) with clinical features of mucopolysaccharidosis type VI (PMID: 1550123, 17458871, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 880). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000000928 | SCV000021078 | pathogenic | Mucopolysaccharidosis, type vi, severe | 1992-04-01 | no assertion criteria provided | literature only |