ClinVar Miner

Submissions for variant NM_024408.4(NOTCH2):c.6909dup (p.Ile2304fs) (rs771237928)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000638604 SCV000760141 pathogenic Hajdu-Cheney syndrome 2017-09-29 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the NOTCH2 gene (p.Ile2304Hisfs*9). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 168 amino acids of the NOTCH2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to be de novo in an individual affected with Hajdu-Cheney syndrome (HCS) (PMID: 27312922). Multiple truncating variants in the last exon of NOTCH2 have been reported in individuals with HCS resulting in deletion of the PEST (proline(P), glutamic acid(E), serine(S), threonine(T)) domain at the C-terminus which regulates the Notch intracellular domain (NICD) with ankyrin repeats (PMID: 21378989, 21378985, 8755249). Specifically, PEST domains are implicated in mediating proteosomal degradation of proteins with ankyrin-repeat domains, and loss of this PEST domain is expected to result in a stable, functional but constitutively active NICD in the NOTCH2 protein (PMID: 21378989, 8755249). For these reasons, this variant has been classified as Pathogenic.
Karsan Lab,BC Cancer Agency RCV000208622 SCV000258944 pathogenic Monoclonal B-Cell Lymphocytosis 2015-12-15 no assertion criteria provided research

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