ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.910TTC[1] (p.Phe305del)

dbSNP: rs118192212
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000194164 SCV000247668 pathogenic Seizure 2015-06-26 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000234792 SCV000291976 pathogenic Developmental and epileptic encephalopathy, 7 2016-06-09 criteria provided, single submitter research
GeneDx RCV000414259 SCV000491167 pathogenic not provided 2022-08-05 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect and significant impairment of potassium channel function (Ishii et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; Lost residue is predicted to be within the transmembrane segment S6; This variant is associated with the following publications: (PMID: 20437616, 18640800, 27602407, 28554332, 28728838, 32214227, 35401395)
Mendelics RCV000990332 SCV001141275 pathogenic Seizures, benign familial neonatal, 1 2021-11-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002283 SCV001160166 pathogenic not specified 2018-12-15 criteria provided, single submitter clinical testing De novo occurrence of the p.Phe305del variant has been reported in several individuals (Ishii 2009, Millichap 2016, Sterbova 2017, Bowling 2017, Spagnoli 2018) including identical twins (Millichap 2016). This variant is absent from general population databases including gnomAD but is listed in ClinVar with pathogenic classification (ClinVar ID 211236). The p.Phe305del variant is located in the Kv7.2 channel transmembrane segment 6, in the ion transport domain (IPR005821). Ishii et al. (2009) showed that this variant (reported as Phe304del) leads to null function with no current observed in the mutant KCNQ2 potassium channel. Based on the available evidence, this de novo p.Phe305del KCNQ2 gene variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000414259 SCV001247382 pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing
Invitae RCV001381685 SCV001580178 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2023-07-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe305 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25473036; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this variant affects KCNQ2 function (PMID: 18640800). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 211236). This variant is also known as c.910-2delTTC. This variant has been observed in individual(s) with KCNQ2-related conditions (PMID: 18640800, 27602407, 28728838). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.913_915del, results in the deletion of 1 amino acid(s) of the KCNQ2 protein (p.Phe305del), but otherwise preserves the integrity of the reading frame.
DASA RCV001836639 SCV002097296 pathogenic KCNQ2-related disorder 2022-02-14 criteria provided, single submitter clinical testing Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 18640800) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:211236; PMID: 22884718; 32214227; 28728838; 27602407) - PS4. This variant is not present in population databases (rs118192212, gnomAD; ABraOM no frequency - - PM2. Protein length variants as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants - PM4. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 32214227; 28728838) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
Pediatrics, West China Second University Hospital, Sichuan University RCV000234792 SCV002525867 likely pathogenic Developmental and epileptic encephalopathy, 7 2021-11-16 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV001836639 SCV004710748 pathogenic KCNQ2-related disorder 2024-01-08 criteria provided, single submitter clinical testing The KCNQ2 c.913_915delTTC variant is predicted to result in an in-frame deletion (p.Phe305del). This variant was reported in multiple individuals with KCNQ2-related conditions including benign familial neonatal epilepsy (Ishii et al 2009. PubMed ID: 18640800; reported as p.Phe304del), early infantile epileptic encephalopathy (Hengel et al 2020. PubMed ID: 32214227; Table S1 in Bayat et al 2022. PubMed ID: 35723786; Millichap et al 2016. PubMed ID: 27602407; Table S1 in Vanoye et al 2022. PubMed ID: 35104249), and intellectual disability and developmental delay (Supplementary data in Bowling et al 2017. PubMed ID: 28554332). This variant has interpretations of likely pathogenic and pathogenic in ClinVar ( This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
GeneReviews RCV000678098 SCV000041663 not provided Benign Rolandic epilepsy no assertion provided literature only BECTS (benign childhood epilepsy with centrotemporal spikes)
Section for Clinical Neurogenetics, University of Tübingen RCV000234792 SCV001156087 likely pathogenic Developmental and epileptic encephalopathy, 7 2019-08-01 no assertion criteria provided research
Channelopathy-Associated Epilepsy Research Center RCV003315329 SCV004015101 not provided Complex neurodevelopmental disorder no assertion provided literature only

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