ClinVar Miner

Submissions for variant NM_001081.4(CUBN):c.4376C>G (p.Ser1459Cys)

gnomAD frequency: 0.00032  dbSNP: rs138022214
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414744 SCV000492049 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing The S1459C variant in the CUBN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S1459C variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S1459C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret S1459C as a variant of uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV002480267 SCV002787166 uncertain significance Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign 2022-05-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002523959 SCV003316682 uncertain significance Imerslund-Grasbeck syndrome 2022-07-11 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 373457). This variant has not been reported in the literature in individuals affected with CUBN-related conditions. This variant is present in population databases (rs138022214, gnomAD 0.1%). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1459 of the CUBN protein (p.Ser1459Cys).

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