Submissions for variant NM_172107.4(KCNQ2):c.1093C>T (p.Arg365Ter)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489438	SCV000576498	pathogenic	not provided	2017-05-02	criteria provided, single submitter	clinical testing	The R365X nonsense variant in the KCNQ2 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R365X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although this pathogenic variant has not been reported previously to our knowledge, its presence is consistent with the diagnosis of a KCNQ2-related disorder in this individual.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001004707	SCV001164170	pathogenic	Seizures, benign familial neonatal, 1	2017-06-07	criteria provided, single submitter	clinical testing
Invitae	RCV001070007	SCV001235214	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-01-13	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: 426132). 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.Arg365*) 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).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001004707	SCV002767957	pathogenic	Seizures, benign familial neonatal, 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with early infantile epileptic encephalopathy, 7 (EIEE) (MIM#613720) and benign neonatal seizures, 1 (MIM#121200). Missense variants have been reported with a dominant negative mechanism (OMIM, PMID 24318194) and in patients with either BNS or EEIE. Truncating variants and those predicted to undergo NMD have been reported to cause loss of function (Decipher) and are almost exclusively found in patients with BNS (PMID: 32917465). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, however, this is only reported for patients with BNS (PMID: 25959266). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (Decipher), and have been observed in patients with benign neonatal seizures (BNS) (PMID: 23360469, PMID: 32917465). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign