ClinVar Miner

Submissions for variant NM_001081.4(CUBN):c.4460_4464del (p.Arg1487fs)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826101 SCV000967606 likely pathogenic Megaloblastic anemia due to inborn errors of metabolism 2018-07-18 criteria provided, single submitter clinical testing The p.Arg1487fs variant in CUBN has not been previously reported in individuals with Imerslund-Grasbeck syndrome or megaloblastic anemia, but has been identifie d in 7/126726 European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs770921101). Although this variant has b een seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frames hift, which alters the protein?s amino acid sequence beginning at position 1487 and leads to a premature termination codon 43 amino acids downstream. This alter ation is then predicted to lead to a truncated or absent protein. Loss of functi on of the CUBN gene is an established disease mechanism in autosomal recessive I merslund-Grasbeck syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic . ACMG/AMP criteria applied: PVS1, PM2

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