ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.4801G>A (p.Ala1601Thr)

gnomAD frequency: 0.00004  dbSNP: rs376702277
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000475870 SCV000541835 uncertain significance Neuroblastoma, susceptibility to, 3 2024-12-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1601 of the ALK protein (p.Ala1601Thr). This variant is present in population databases (rs376702277, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 404328). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Fulgent Genetics, Fulgent Genetics RCV000475870 SCV000896999 uncertain significance Neuroblastoma, susceptibility to, 3 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV002339111 SCV002636416 likely benign Hereditary cancer-predisposing syndrome 2022-01-07 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV004591286 SCV005080481 uncertain significance not provided 2023-05-15 criteria provided, single submitter clinical testing 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
Breakthrough Genomics, Breakthrough Genomics RCV004591286 SCV005187595 uncertain significance not provided criteria provided, single submitter not provided
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000475870 SCV005402195 uncertain significance Neuroblastoma, susceptibility to, 3 2024-01-29 criteria provided, single submitter clinical testing The ALK c.4801G>A (p.Ala1601Thr) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with ALK-related neuroblastic tumor susceptibility. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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