ClinVar Miner

Submissions for variant NM_001122630.2(CDKN1C):c.719_730delinsGTGC (p.Ala240fs) (rs1554937726)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549523 SCV000623178 likely pathogenic Beckwith-Wiedemann syndrome 2017-07-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CDKN1C gene (p.Ala251Glyfs*32). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acids of the CDKN1C protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDKN1C-related disease. This truncation is expected to disrupt the C-terminal QT domain (residues 236-316) of the CDKN1C protein, including PCNA binding domain that is required for inhibiting cell transformation and cellular localization (PMID: 7729683, 9465025, 21816904, 23719190). A different truncation downstream of this variant (p.Arg282*) has been determined to be pathogenic (PMID: 26077438, 19386358, 10424811). This suggests that deletion of this region of the CDKN1C protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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