rs864321707

chr20-63439608-G-Achr20-63439608-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_172107.4(KCNQ2):c.917C>T(p.Ala306Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A306P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ2 NM_172107.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:2
• Conservation: PhyloP100: 7.88

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 17 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_172107.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-63439609-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 205888.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, 0.988
• PP5: Variant 20-63439608-G-A is Pathogenic according to our data. Variant chr20-63439608-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 219235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63439608-G-A is described in Lovd as [Pathogenic]. Variant chr20-63439608-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ2	NM_172107.4	c.917C>T	p.Ala306Val	missense_variant	6/17	ENST00000359125.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ2	ENST00000359125.7	c.917C>T	p.Ala306Val	missense_variant	6/17	1	NM_172107.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460142 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2022	This substitution is predicted to be within the transmembrane segment S6; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 27535030, 23708187, 32139178, 34120799, 29390993, 26704558, 25959266, 29455050, 31780880, 34055682, 29852413) -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 04, 2022	The KCNQ2 c.917C>T (p.Ala306Val) missense variant results in the substitution of alanine at amino acid position 306 with valine. This variant has been reported in at least seven individuals with an early onset epilepsy phenotype, including in one case also associated with sudden unexpected death (PMID: 29390993; PMID: 32139178; PMID: 29455050; PMID: 32917465; PMID: 27535030; PMID: 31780880; PMID: 25959266; PMID: 26704558; PMID: 29852413; PMID: 34120799; PMID: 34055682). In four of these individuals the variant was reported to have occurred de novo (PMID: 34120799; PMID: 29852413; PMID: 27535030; PMID: 29390993). Another variant at the same amino acid position, c.916G>A p.Ala306Thr, has been reported in a heterozygous state in three probands, two with benign familial neonatal convulsions, both individuals inheriting the variant from affected parents (PMID: 9425895; PMID: 24375629). In the third proband the p.Ala306Thr variant was reported to have occurred de novo in a male child with infantile spasm, developmental delay and hypotonia but without epileptic seizures (PMID: 26138355). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.917C>T (p.Ala306Val) variant is classified as pathogenic for KCNQ2-related disorders. -

Developmental and epileptic encephalopathy, 7 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.A306V in KCNQ2 (NM_172107.4) has been reported in multiple individuals with Otahara syndrome, wherein it was proved to be de novo in some patients(Rim JH et al,Hortigüela M et al). The variant has been submitted to ClinVar as Pathogenic.The p.A306V variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.A306V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 306 of KCNQ2 is conserved in all mammalian species. The nucleotide c.917 in KCNQ2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	-	- -
not provided, no classification provided	literature only	GeneReviews	-	EE (epileptic encephalopathy) -

KCNQ2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 29, 2022

Variant summary: KCNQ2 c.917C>T (p.Ala306Val) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250792 control chromosomes. c.917C>T has been reported in the literature in individuals affected with early onset epileptic encephalopathy and Ohtahara syndrome, and in multiple cases was reported as a de novo variant (Ko_2018, Kothur_2018, Fernandez-Marmiesse_2018, Sun_2021, Shellhaas_2017, Bagnall_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants affecting codon 306 have been reported in association with Epilepsy and/or neurodevelopmental disorders in HGMD (A306P, A306T). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 15, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala306 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9425895, 19453707, 26138355). 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: 219235). This missense change has been observed in individual(s) with early onset epileptic encephalopathy and Ohtahara syndrome (PMID: 25959266, 26704558, 27535030, 29390993). 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 306 of the KCNQ2 protein (p.Ala306Val). -

Autosomal recessive congenital ichthyosis 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.S53W in PNPLA1 (NM_001145717.1) has been previously reported in homozygous state in an affected patient. The patient had a collodion membrane at birth (Boyden LM et al).The variant has been submitted to ClinVar as Pathogenic based on the same. The p.S53W variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between serine and tryptophan, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. For these reasons, this variant has been classified as Likely Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Complex neurodevelopmental disorder Other:1

not provided, no classification provided

literature only

Channelopathy-Associated Epilepsy Research Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.;.;.;.;.;H;.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
Sift4G	Uncertain	0.026	D;D;D;D;D;.;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.;D;.;D;D;.
Vest4		0.97
MutPred		0.90		Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);.;Loss of catalytic residue at A306 (P = 0.4461);.;Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);Loss of catalytic residue at A306 (P = 0.4461);
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.90
gMVP		1.0

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: rs864321707; hg19: chr20-62070961; COSMIC: COSV60436134; COSMIC: COSV60436134;