rs587777219

chr20-63442428-G-Achr20-63442428-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_172107.4(KCNQ2):c.794C>T(p.Ala265Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A265P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 9.77

Genes affected

KCNQ2 (HGNC:6296): (potassium voltage-gated channel subfamily Q member 2) The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_172107.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-63442429-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 197891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, KCNQ2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 20-63442428-G-A is Pathogenic according to our data. Variant chr20-63442428-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 120176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63442428-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.794C>T	p.Ala265Val	missense_variant	5/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.794C>T	p.Ala265Val	missense_variant	5/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 7 Pathogenic:4 Other:1

not provided, no classification provided	literature only	GeneReviews	-	EE (epileptic encephalopathy) -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Oct 01, 2021	This sequence change in KCNQ2 is predicted to replace alanine with valine at codon 265 (p.(Ala265Val)). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in the transmembrane ion transport domain in a region, amino acids 1-369, that is highly constrained. There is a moderate physicochemical difference between alanine and valine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been identified as a de novo occurrence with confirmed parental relationships in 3 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with Ohtahara syndrome or undetermined neonatal epileptic encephalopathy (NEE; PMID: 22926866, 23621294, 25959266, 32362866, 34354098). It has also been identified in 2 individuals with NEE and unknown de novo status (PMID: 25959266, 34395220). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Another missense variant c.793G>A, p.Ala265Thr in the same codon has been classified as pathogenic for NEE (ClinVar Variation ID: 197891). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS2/PM6_Strong, PM1, PM5, PS4_Supporting, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jun 26, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2022	The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22926866, 23621294, 28867141, 30185235, 31036916, 31418850, 32362866, 32139178, 32917465, 33098118, 32712949, 31785789, 27602407) -

KCNQ2-Related Disorders Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Jun 27, 2017

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2017

The p.A265V variant (also known as c.794C>T), located in coding exon 5 of the KCNQ2 gene, results from a C to T substitution at nucleotide position 794. The alanine at codon 265 is replaced by valine, an amino acid with similar properties. This variant as been observed de novo in unrelated patients with early onset epileptic encephalopathy (Saitsu H et al. Ann. Neurol., 2012 Aug;72:298-300; Milh M et al. Am. J. Med. Genet. A, 2015 Oct;167A:2314-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 25, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala265 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22275249, 23692823, 27535030, 27602407, 27779742). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ2 protein function. ClinVar contains an entry for this variant (Variation ID: 120176). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 22926866, 30185235). 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 sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 265 of the KCNQ2 protein (p.Ala265Val). -

Intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Dec 01, 2017

- -

Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Nov 11, 2021

KCNQ2 NM_172107 exon 5 p.Ala265Val (c.794C>T): This variant has been reported in the literature in at least 2 individuals (1 with early onset epileptic encephalopathy and 1 with Ohtahara syndrome), both of whom were reported as de novo (Saitsu 2012 PMID:2292866, Kato 2013 PMID:23621294). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:120176). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, other variants at this position (p.Ala265Thr, p.Ala265Pro) have been reported in association with disease, suggesting that this codon has functional significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;M;.;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;D;D;D;D;D;D
Polyphen		0.78	P;.;.;.;.;.;P;.;P;P;.;.
Vest4		0.87
MutPred		0.76		Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);.;Loss of disorder (P = 0.0801);.;Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);.;
MVP		1.0
MPC		2.3
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.82
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587777219; hg19: chr20-62073781; COSMIC: COSV60431805; COSMIC: COSV60431805;