ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.1645G>A (p.Glu549Lys)

gnomAD frequency: 0.00003  dbSNP: rs1388997240
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001056216 SCV001220644 uncertain significance Neuroblastoma, susceptibility to, 3 2023-09-20 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 851756). 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 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 549 of the ALK protein (p.Glu549Lys).
Sema4, Sema4 RCV002256670 SCV002528398 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-26 criteria provided, single submitter curation
Ambry Genetics RCV002256670 SCV002704622 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-04 criteria provided, single submitter clinical testing The p.E549K variant (also known as c.1645G>A), located in coding exon 8 of the ALK gene, results from a G to A substitution at nucleotide position 1645. The glutamic acid at codon 549 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV004768828 SCV005377579 uncertain significance not provided 2023-12-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.

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