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

dbSNP: rs118192212

Total submissions: 14

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
Labcorp Genetics (formerly Invitae), Labcorp	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 - http://abraom.ib.usp.br/) - 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001836639	SCV005884372	pathogenic	KCNQ2-related disorder	2024-12-26	criteria provided, single submitter	clinical testing	Variant summary: KCNQ2 c.913_915delTTC (p.Phe305del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 250852 control chromosomes. c.913_915delTTC has been reported as de novo variant in the literature in individuals affected with KCNQ2-Related Disorders. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 35723786, 18640800). ClinVar contains an entry for this variant (Variation ID: 211236). Based on the evidence outlined above, the variant was classified 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
PreventionGenetics, part of Exact Sciences	RCV001836639	SCV004710748	pathogenic	KCNQ2-related disorder	2024-01-08	no assertion criteria provided	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 (https://www.ncbi.nlm.nih.gov/clinvar/variation/211236/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.