ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.3574C>T (p.Arg1192Trp) (rs534852056)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000647386 SCV000769182 uncertain significance Neuroblastoma 3 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1192 of the ALK protein (p.Arg1192Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs534852056, ExAC 0.003%). This variant has not been reported in the literature in individuals with ALK-related disease. ClinVar contains an entry for this variant (Variation ID: 538184). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg1192Pro) has been determined to be pathogenic (PMID: 18724359, 18923523). This suggests that the arginine residue is critical for ALK protein function and that other missense substitutions at this position may also be pathogenic. 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 RCV001020643 SCV001182149 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-24 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV000647386 SCV001299376 uncertain significance Neuroblastoma 3 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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