Submissions for variant NM_172107.4(KCNQ2):c.856dup (p.Gln286fs)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627637	SCV000748637	likely pathogenic	not provided	2018-04-25	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the KCNQ2 gene. The c.856dupC variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.856dupC variant causes a frameshift starting with codon Glutamine 286, changes this amino acid to a Proline residue and creates a premature Stop codon at position 45 of the new reading frame, denoted p.Gln286ProfsX45. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.856dupC variant is not observed in large population cohorts (Lek et al., 2016). Additionally, other loss-of-function variants downstream of this position have been reported in the Human Gene Mutation Database in individuals with KCNQ2-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV002529812	SCV003241675	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-10-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 524140). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln286Profs*45) in the KCNQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157, 23692823, 27779742).

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