ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.3824G>A (p.Arg1275Gln)

dbSNP: rs113994087
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268655 SCV001447738 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Department of Pediatrics, Memorial Sloan Kettering Cancer Center RCV000019709 SCV001478107 pathogenic Neuroblastoma, susceptibility to, 3 2020-12-15 criteria provided, single submitter research
Invitae RCV000019709 SCV002224310 pathogenic Neuroblastoma, susceptibility to, 3 2023-04-19 criteria provided, single submitter clinical testing Experimental studies have shown that this missense change affects ALK function (PMID: 18923523, 18923525). For these reasons, this variant has been classified as Pathogenic. 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: 18083). This missense change has been observed in individual(s) with neuroblastoma (PMID: 18724359, 18923523, 18923525, 29489754, 30350464; 18724359.). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1275 of the ALK protein (p.Arg1275Gln).
Ambry Genetics RCV002354167 SCV002619803 pathogenic Hereditary cancer-predisposing syndrome 2022-04-29 criteria provided, single submitter clinical testing The p.R1275Q pathogenic mutation (also known as c.3824G>A), located in coding exon 25 of the ALK gene, results from a G to A substitution at nucleotide position 3824. The arginine at codon 1275 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in the germline of several unrelated families with neuroblastoma and confirmed de novo in at least one affected individual (Mossé YP et al. Nature, 2008 Oct;455:930-5, Janoueix-Lerosey I et al. Nature, 2008 Oct;455:967-70, Kudo K et al. Genes Chromosomes Cancer, 2018 12;57:665-669, Ambry internal data). In addition, this alteration has been shown to constitutively activate the ALK tyrosine kinase domain using a peptide phosphorylation assay (Bresler SC et al. Sci Transl Med, 2011 Nov;3:108ra114). Furthermore, this alteration was able to drive the transformation of NIH/3T3 cells in a transformation assay (Bresler SC et al. Cancer Cell, 2014 Nov;26:682-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM RCV000019709 SCV000040007 risk factor Neuroblastoma, susceptibility to, 3 2012-03-01 no assertion criteria provided literature only
GeneReviews RCV000019709 SCV000041068 not provided Neuroblastoma, susceptibility to, 3 no assertion provided literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000019709 SCV000256824 pathogenic Neuroblastoma, susceptibility to, 3 2015-10-07 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000432041 SCV000503769 pathogenic Neuroblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440978 SCV000503770 likely pathogenic Neoplasm of brain 2014-12-26 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423720 SCV000503771 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only

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