ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.3421G>A (p.Asp1141Asn) (rs748493584)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780827 SCV000918417 uncertain significance not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: ALK c.3421G>A (p.Asp1141Asn) results in a conservative amino acid change located in the Catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 277056 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3421G>A has been reported in the literature in individuals with limited available information (Bavi_2013, Siraj_2017). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on doxorubicin-induced apoptosis. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000527321 SCV000648695 uncertain significance Neuroblastoma 3 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1141 of the ALK protein (p.Asp1141Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs748493584, ExAC 0.01%). This variant has been observed in individuals affected with colorectal cancer (PMID: 28975465). ClinVar contains an entry for this variant (Variation ID: 470828). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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