ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.2278del (p.Arg760fs) (rs1555850590)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000543835 SCV000634064 likely pathogenic Early infantile epileptic encephalopathy 2017-04-23 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 17 of the KCNQ2 mRNA (c.2278delC), causing a frameshift at codon 760. This creates a frameshift in the last exon of the KCNQ2 mRNA (p.Arg760Alafs*170). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 113 amino acids of the KCNQ2 protein, and to extend the protein by an additional 56 amino acids. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNQ2-related disease. Two different frameshift variants downstream of this position (c.2597delG, also known as 2513delG, and c.2605_2609dup, also known as 867insGGGCC or 2516ins5) have been determined to be pathogenic (PMID: 10482260, 14534157, 21937445). An experimental study has shown that the these frameshift variants create a novel RCXRG motif in the altered C-terminal sequence that targets the protein for degradation (PMID: 21937445). The C-terminal extension of this c.2287delC variant also contains an RCXRG motif, suggesting that it too would be subject to degradation. In summary, this variant is a novel deletion that creates a frameshift similar to previously reported KCNQ2 variants. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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