ClinVar Miner

Submissions for variant NM_004974.4(KCNA2):c.1265_1266del (p.Glu422fs) (rs1064796294)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478745 SCV000572866 likely pathogenic not provided 2017-01-30 criteria provided, single submitter clinical testing The c.1265_1266delAG variant in the KCNA2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Glutamic Acid 422, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Glu422GlyfsX21. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 78 amino acids of the protein are replaced by 20 incorrect amino acids. The c.1265_1266delAG 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. The c.1265_1266delAG variant is a strong candidate for a pathogenic variant
Invitae RCV001233488 SCV001406085 likely pathogenic Epileptic encephalopathy, early infantile, 32 2020-07-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the KCNA2 gene (p.Glu422Glyfs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acids of the KCNA2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 31054490). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 423204). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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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