ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.4811A>G (p.Tyr1604Cys)

gnomAD frequency: 0.00004  dbSNP: rs372440265
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000229633 SCV000288371 uncertain significance Neuroblastoma, susceptibility to, 3 2024-08-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1604 of the ALK protein (p.Tyr1604Cys). This variant is present in population databases (rs372440265, gnomAD 0.02%). 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: 239845). 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. 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 RCV002338734 SCV002636475 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-29 criteria provided, single submitter clinical testing The p.Y1604C variant (also known as c.4811A>G), located in coding exon 29 of the ALK gene, results from an A to G substitution at nucleotide position 4811. The tyrosine at codon 1604 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV003390993 SCV004118837 uncertain significance ALK-related disorder 2023-07-03 criteria provided, single submitter clinical testing The ALK c.4811A>G variant is predicted to result in the amino acid substitution p.Tyr1604Cys. To our knowledge, this variant has not been reported in the literature in affected individuals. This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-29416142-T-C) and is reported in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/239845/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics RCV000229633 SCV004190469 uncertain significance Neuroblastoma, susceptibility to, 3 2023-06-22 criteria provided, single submitter clinical testing
GeneDx RCV004725110 SCV005332600 uncertain significance not provided 2024-03-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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