Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000596238 | SCV001225936 | pathogenic | not provided | 2023-03-29 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 499244). This variant has been observed in individuals with clinical features of sialidosis (Invitae). This variant is present in population databases (rs781137251, gnomAD 0.01%). This sequence change affects codon 205 of the NEU1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NEU1 protein. This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. |
| Victorian Clinical Genetics Services, |
RCV002470921 | SCV002768165 | pathogenic | Sialidosis type 2 | 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 sialidosis types I and II (MIM#256550). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Type I is milder and presents later onset compared to type II (OMIM, PMID: 35036219). (I) 0210 - Splice site variant proven to affect splicing of the transcript with an effect on protein sequence. Studies using cultured fibroblasts from this individual detected five mis-splicing events all causing nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). The main event detected was the activation of a cryptic donor splice site in exon 3 that is predicted to result in p.Gly203Glufs*30 (Splicing Diagnostics, Kids Neuroscience Centre). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2) for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0702 - Other variants predicted to cause NMD comparable to the one identified in this case have strong previous evidence for pathogenicity (DECIPHER). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported VUS in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1005 - Clinically accredited laboratory assay specific to gene product shows abnormal protein function. Biochemical studies using cultured fibroblasts from this individual showed zero activity of neuraminidase (Report ID: 397993113). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Eurofins Ntd Llc |
RCV000596238 | SCV000704637 | uncertain significance | not provided | 2016-12-20 | flagged submission | clinical testing |