ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.3692G>A (p.Arg1231Gln) (rs200110351)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569692 SCV000672478 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000474175 SCV000541872 uncertain significance Neuroblastoma 3 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1231 of the ALK protein (p.Arg1231Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs200110351, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with neuroblastoma (PMID: 25517749). ClinVar contains an entry for this variant (Variation ID: 404363). Experimental studies have shown that this missense variant does not affect the tyrosine phosphorylation activity of the ALK protein (PMID: 25517749, 25874976). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.

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