ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.623T>C (p.Ile208Thr)

gnomAD frequency: 0.00001  dbSNP: rs372226787
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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 RCV001037225 SCV001200627 uncertain significance Neuroblastoma, susceptibility to, 3 2024-12-22 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 208 of the ALK protein (p.Ile208Thr). This variant is present in population databases (rs372226787, gnomAD 0.0009%). 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: 836167). 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 tolerated. 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.
Ambry Genetics RCV002363554 SCV002658664 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-06 criteria provided, single submitter clinical testing The p.I208T variant (also known as c.623T>C), located in coding exon 1 of the ALK gene, results from a T to C substitution at nucleotide position 623. The isoleucine at codon 208 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital RCV003313172 SCV004012937 uncertain significance Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype 2018-10-09 criteria provided, single submitter research
GeneDx RCV004768797 SCV005378190 uncertain significance not provided 2023-10-30 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

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