rs796052676

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_004519.4(KCNQ3):c.688C>T(p.Arg230Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R230H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNQ3
NM_004519.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:2

Conservation

PhyloP100: 6.79

Variant links:

Genes affected

KCNQ3 (HGNC:6297): (potassium voltage-gated channel subfamily Q member 3) This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

KCNQ3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a transmembrane_region Helical; Voltage-sensor; Name=Segment S4 (size 21) in uniprot entity KCNQ3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_004519.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-132180245-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 8-132180246-G-A is Pathogenic according to our data. Variant chr8-132180246-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 205963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132180246-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4 link	c.688C>T	p.Arg230Cys	missense_variant	Exon 4 of 15	ENST00000388996.10	NP_004510.1	O43525-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10 link	c.688C>T	p.Arg230Cys	missense_variant	Exon 4 of 15	1	NM_004519.4	ENSP00000373648.3		O43525-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727192

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Seizures, benign familial neonatal, 2

Pathogenic:10Other:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNQ3 c.688C>T (p.Arg230Cys) variant is a missense variant that has a well-documented association with KCNQ3-related disorders. Across a selection of the available literature, it has been reported in at least eight individuals with features that included intellectual disability, autism, EEG abnormalities, seizures, staring spells, strabismus, hypotonia, and structural abnormalities on brain MRI (Rauch et al. 2012; Epi4K Consortium et al. 2013; Deciphering Developmental Disorders Study 2017; Geisheker et al. 2017; Lindy et al. 2018; Trinh et al. 2019; Sands et al. 2019; Valentino et al. 2021). In at least four of these individuals, the variant occurred de novo. The p.Arg230Cys variant is not reported in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggest the variant is rare. In vitro analyses have demonstrated that this variant, which affects a crucial gating residue in the S4 transmembrane segment, stabilizes the activated state of the channel, allowing current to flow throughout the physiological voltage range and resulting in gain of function (Miceli et al. 2015; Barro-Soria 2019; Sands et al. 2019). Additional amino acid changes affecting this residue have also been reported in association with KCNQ3-related disorders (Landrum et al. 2016). Based on the available evidence, the p.Arg230Cys variant is classified as pathogenic for KCNQ3-related disorders. -

Jun 08, 2017

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 03, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This study shows that diverse genetic causes underlie CVI. -

Jul 30, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2_Very Strong, PS3, PS4, PM1, PM2, PM5 -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. -

Aug 03, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP3 supporting -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Variant found in 4 unrelated persons, all de novo, in studies focused on different phenotypes -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:3

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a gain-of-function stabilization of the ion channel's activated state (Miceli et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23020937, 26350515, 25740509, 31036916, 31238879, 23934111, 28628100, 28135719, 29655203, 28191890, 31177578, 31618753, 31981491, 31175295, 31785789, 33004838, 27535533) -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ3: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP2, PP3 -

Intellectual disability

Pathogenic:2

May 13, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 20, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jan 06, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.688C>T (p.R230C) alteration is located in exon 4 (coding exon 4) of the KCNQ3 gene. This alteration results from a C to T substitution at nucleotide position 688, causing the arginine (R) at amino acid position 230 to be replaced by a cysteine (C). for KCNQ3-related neurodevelopmental disorder. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in individual(s) with features consistent with KCNQ3-related neurodevelopmental disorder; in at least one individual, it was determined to be de novo (Ehtesham, 2022; Aguilera, 2021; Ziats, 2020; Sands, 2019; Lindy, 2018; Deciphering Developmental Disorders, 2017; Bosch, 2016). Other variant(s) at the same codon, c.688C>A (p.R230S) and c.689G>A ( p.R230H) have been identified in individual(s) with features consistent with KCNQ3-related neurodevelopmental disorder (Grozeva, 2015; Sands, 2019; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

KCNQ3-related developmental disability

Pathogenic:1

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign neonatal seizures

Pathogenic:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 230 of the KCNQ3 protein (p.Arg230Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurodevelopmental disorders and early-onset epileptic encephalopathy (PMID: 23020937, 23934111, 26350515, 28135719, 28628100, 29655203). In at least one individual the variant was observed to be de novo. This variant is also known as p.Arg110Cys, g.133192493G>A. ClinVar contains an entry for this variant (Variation ID: 205963). 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 KCNQ3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNQ3 function (PMID: 25740509, 30578330). For these reasons, this variant has been classified as Pathogenic. -

Intellectual disability, severe

Pathogenic:1

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Neurodevelopmental disorder

Pathogenic:1

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with benign neonatal seizures 2 (MIM#121201) and neurodevelopmental disorder (MONDO:0700092), KCNQ3-related, respectively. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been noted for benign neonatal seizures 2 (MIM#121201) (PMID: 24851285). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic/pathogenic in more than ten individuals, with five reports stating the variant was de novo (ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Many functional analyses on this variant, R230C, have shown that this is a crucial gating residue in the S4 transmembrane segment where the variant stabilises the activated state of the channel, resulting in a gain of function effect (PMIDs: 31177578, 30578330, 25740509). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Seizures, benign familial infantile, 5

Pathogenic:1

Aug 28, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KCNQ3-related Autism and developmental disability

Pathogenic:1

Feb 03, 2020

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The de novo missense variant c.688C>T, p.Arg230Cys identified in this individual has been reported as de novo variant in several patients with Neurodevelopmental disability (nonverbal, with autism spectrum disorder or autistic features and multifocal status epilepticus during sleep) [PMID: 31177578].The p.Arg230Cys is situated in the mutational hotspot of KCNQ3 gene, and functional studies indicate that it causes a gain-of-function stabilization of the ion channel's activated state [PMID: 31177578; PMID: 25740509]. Patients with p.Arg230Cys variant are usually ambulatory by 2 years of age, but were either nonverbal or had single words only and were cognitively impaired with ASD or autistic features [PMID: 31177578; PMID: 31238879].This variant is also not reported in gnomAD database, indicating this is a rare allele. Based on the available evidence, the de novo missense variant c.688C>T, p.Arg230Cys in the KCNQ3 gene is classified as pathogenic. -

Severe neurodevelopmental delay

Pathogenic:1

Jul 10, 2019

Genetics Laboratory - UDIAT Centre Diagnòstic, Hospital Universitari Parc Tauli

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign neonatal seizures;C0238111:Lennox-Gastaut syndrome;C3714756:Intellectual disability

Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 10-08-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.;.;.;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;D;D;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.;.;.;.

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.6

D;.;D;D;.

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;.;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

D;.;.;D;.

Vest4

0.95

MutPred

0.89

Loss of MoRF binding (P = 0.0045);.;.;Loss of MoRF binding (P = 0.0045);.;

MVP

0.99

MPC

2.4

ClinPred

1.0

GERP RS

5.5

Varity_R

0.92

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over