Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000474981 | SCV000541818 | uncertain significance | Neuroblastoma, susceptibility to, 3 | 2023-10-23 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 23 of the ALK gene. It does not directly change the encoded amino acid sequence of the ALK protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 404311). 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 is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV001020792 | SCV001182318 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-10-03 | criteria provided, single submitter | clinical testing | The c.3646-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 24 in the ALK gene. This nucleotide position is well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to weaken the efficiency of the native splice acceptor site, but is not predicted to have a deleterious effect on this splice acceptor/donor site by BDGP; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV003322769 | SCV004028223 | uncertain significance | not provided | 2023-02-15 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. |