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

dbSNP: rs1064796294

Total submissions: 3

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001233488	SCV001406085	pathogenic	Developmental and epileptic encephalopathy, 32	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu422Glyfs*21) in the KCNA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the KCNA2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 31054490; internal data). 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. For these reasons, this variant has been classified as Pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV004546507	SCV005040960	pathogenic	Seizure	2024-02-15	criteria provided, single submitter	clinical testing