ClinVar Miner

Submissions for variant NM_004304.5(ALK):c.4723C>T (p.Arg1575Cys)

gnomAD frequency: 0.00002  dbSNP: rs148351049
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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 RCV001880853 SCV002142770 uncertain significance Neuroblastoma, susceptibility to, 3 2023-01-24 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1377825). This variant has not been reported in the literature in individuals affected with ALK-related conditions. This variant is present in population databases (rs148351049, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1575 of the ALK protein (p.Arg1575Cys). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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 RCV002334789 SCV002639241 uncertain significance Hereditary cancer-predisposing syndrome 2022-04-02 criteria provided, single submitter clinical testing The p.R1575C variant (also known as c.4723C>T), located in coding exon 29 of the ALK gene, results from a C to T substitution at nucleotide position 4723. The arginine at codon 1575 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV003318696 SCV004022946 uncertain significance not provided 2023-01-24 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
PreventionGenetics, part of Exact Sciences RCV003407876 SCV004112502 uncertain significance ALK-related disorder 2023-01-31 criteria provided, single submitter clinical testing The ALK c.4723C>T variant is predicted to result in the amino acid substitution p.Arg1575Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.018% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-29416230-G-A). In ClinVar, this variant is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/1377825/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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