ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.3509T>A (p.Ile1170Asn)

dbSNP: rs1553394197
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000533103 SCV000648698 uncertain significance Neuroblastoma, susceptibility to, 3 2017-07-17 criteria provided, single submitter clinical testing This missense change is located within the functionally conserved tyrosine kinase domain of the ALK protein, where a significant number of previously reported somatic and germline ALK missense mutations have been reported (PMID: 18724359, 21972109, 18923524). One experimental study has shown that this variant accelerated the autophosphorylation of the ALK tyrosine kinase domain in vitro, which is necessary for its activation (PMID: 25517749). In summary, this variant has been shown to disrupt protein function in vitro. However, further genetic data is necessary at this point to unequivocally classify this variant. Therefore, it has been classified as a Variant of Uncertain Significance. This has not been reported in the literature in the germline of individuals with an ALK-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with asparagine at codon 1170 of the ALK protein (p.Ile1170Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine.

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