Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000647449 | SCV000769245 | uncertain significance | Neuroblastoma, susceptibility to, 3 | 2023-06-20 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Arg1192 amino acid residue in ALK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18724359, 18923523, 21838707, 22071890). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ALK function (PMID: 26002608). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 538242). This variant has not been reported in the literature in individuals affected with ALK-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1192 of the ALK protein (p.Arg1192Gly). |
| Ambry Genetics | RCV001020642 | SCV001182148 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-12-28 | criteria provided, single submitter | clinical testing | The p.R1192G variant (also known as c.3574C>G), located in coding exon 23 of the ALK gene, results from a C to G substitution at nucleotide position 3574. The arginine at codon 1192 is replaced by glycine, an amino acid with dissimilar properties. In a functional study, this alteration showed increased levels of ALK phosphorylation and increased transformative activity compared to wild-type ALK, and also displayed sensitivity to ALK inhibitors (Togashi Y et al. Ann. Oncol., 2015 Aug;26:1800-1). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |