Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000000949 | SCV002243058 | pathogenic | Mucopolysaccharidosis type 7 | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change affects codon 539 of the GUSB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GUSB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs377519272, gnomAD 0.008%). This variant has been observed in individual(s) with mucopolysaccharidosis (MPS) VII (PMID: 7633414, 30442200). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 901). Studies have shown that this variant results in aberrant splicing and introduces a premature termination codon (PMID: 7633414, 30442200). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV000000949 | SCV002768930 | pathogenic | Mucopolysaccharidosis type 7 | 2022-03-31 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mucopolysaccharidosis VII (MIM#253220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR studies have shown that this variant creates a cryptic donor splice site that leads to two abnormal splicing outcomes - partial skipping of exon 10 and complete skipping of exon 9. Both of these abnormal splicing events cause out of frame deletions and NMD-predicted frameshifts, p.(Ser539Argfs*8) for partial exon 10 skipping and p.(Met465Leufs*6) for exon 9 skipping (PMIDs: 30442200, 7633414). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, PMID: 19224584). (SP) 0803 - This variant has limited previous evidence of pathogenicity in two unrelated individuals. This variant has been observed as compound heterozygous in one individual and as homozygous in another with mucopolysaccharidosis (PMIDs: 30442200, 7633414). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in fibroblasts found variant protein had significantly reduced enzyme activity compared to wild type protein (PMID: 7633414). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Fulgent Genetics, |
RCV000000949 | SCV002785612 | likely pathogenic | Mucopolysaccharidosis type 7 | 2021-08-11 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000000949 | SCV000021099 | pathogenic | Mucopolysaccharidosis type 7 | 1995-04-01 | no assertion criteria provided | literature only |