ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.1184G>A (p.Arg395His)

gnomAD frequency: 0.00006  dbSNP: rs769910087
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000560261 SCV000648600 uncertain significance Neuroblastoma, susceptibility to, 3 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 395 of the ALK protein (p.Arg395His). This variant is present in population databases (rs769910087, gnomAD 0.008%). 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: 470740). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine 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 RCV000560261 SCV000897005 uncertain significance Neuroblastoma, susceptibility to, 3 2018-10-31 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV002258962 SCV002528381 likely benign Hereditary cancer-predisposing syndrome 2021-09-30 criteria provided, single submitter curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000560261 SCV002584548 uncertain significance Neuroblastoma, susceptibility to, 3 2022-08-15 criteria provided, single submitter clinical testing The ALK c.1184G>A (p.Arg395His) missense change has a maximum subpopulation frequency of 0.0080% 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 the literature 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.
GeneDx RCV003325492 SCV004031744 uncertain significance not provided 2023-10-04 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; This variant is associated with the following publications: (PMID: 29617658, 35865984)
Baylor Genetics RCV000560261 SCV004195385 uncertain significance Neuroblastoma, susceptibility to, 3 2024-03-21 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003325492 SCV004238568 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing

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