ClinVar Miner

Submissions for variant NM_001081.3(CUBN):c.1865del (p.Thr622fs) (rs386833771)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000321365 SCV000329945 pathogenic not provided 2018-04-10 criteria provided, single submitter clinical testing The c.1865delC pathogenic variant in the CUBN gene has been reported previously, with another variant, in association with inherited cobalamin malabsorption (Tanner et al., 2012). The c.1865delC variant causes a frameshift starting with codon Threonine 622, changes this amino acid to a Isoleucine residue, and creates a premature Stop codon at position 7 of the new reading frame, denoted p.Thr622IlefsX7. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1865delC variant was not observed 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. We interpret c.1865delC as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000321365 SCV000861332 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285659 SCV001472127 pathogenic none provided 2019-08-23 criteria provided, single submitter clinical testing The CUBN c.1865delC; p.Thr622fs variant (rs386833771) is reported in the literature in an individual affected with a hereditary vitamin B12 deficiency syndrome that also carried a second frameshift variant (Tanner 2012). The c.1865delC variant is found on only three chromosomes in the Genome Aggregation Database (3/282742 alleles), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Tanner SM et al. Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. Orphanet J Rare Dis. 2012 Aug 28;7:56.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049735 SCV000082142 probable-pathogenic Imerslund-Gräsbeck syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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