8-132180245-C-T

Variant names:

• chr8-132180245-C-T
• rs749205120
• NM_004519.4:c.689G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004519.4(KCNQ3):​c.689G>A​(p.Arg230His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 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. R230C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ3 NM_004519.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.91
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• seizures, benign familial neonatal, 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign neonatal seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr8-132180246-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 205963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 8-132180245-C-T is Pathogenic according to our data. Variant chr8-132180245-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 424397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ3	NM_004519.4	c.689G>A	p.Arg230His	missense_variant	Exon 4 of 15	ENST00000388996.10	NP_004510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ3	ENST00000388996.10	c.689G>A	p.Arg230His	missense_variant	Exon 4 of 15	1	NM_004519.4	ENSP00000373648.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251138 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Dec 09, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a gain-of-function change (PMID: 31177578); 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; This variant is associated with the following publications: (PMID: 31177578, 30578330, 33794528, 32506321, 34728568, 31981491, 35982160, 37776660, 35982159, 35723786) -

Jul 31, 2017

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;provider interpretation

This 13 year old male with intellectual disability was found to carry a de novo variant in the KCNQ3 gene. He reportedly has a history of staring spells (beginning at age 6) and at time of submission, is being evaluated for a new seizure-like event. An EEG at age 12 was abnormal; discharges were considered epileptiform and reflected a lowered seizure threshold for partial and secondary generalized forms of epilepsy. The spectrum of KCNQ3-Related Disorders includes benign familial neonatal epilepsy, benign familial infantile epilepsy, and intellectual disability with or without seizures and/or cortical visual impairment. Given this patient's lack of early onset seizure activity, he likely falls in the third category, which is not as robustly phenotyped at the current time. Different missense variants at this same position (p.Arg230Cys, p.Arg230Ser) have been reported in individuals with non-syndromic intellectual disability and individuals with benign familial neonatal seizures. The variant occurs at a conserved position predicted to be within the transmembrane segment S4 voltage sensor, and in silico analysis predicts this variant is probably damaging to the protein structure/function. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ3: PM1:Strong, PS4, PS3:Moderate, PP3, PS1:Supporting, PS2:Supporting -

Seizures, benign familial neonatal, 2 Pathogenic:4

Mar 28, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jun 19, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant and other missense changes at the same p.Arg230 residue have been previously reported as de novo changes in patients with autism, developmental disability and in some cases, multifocal status epilepticus during sleep (PMID: 31177578). The p.Arg230 residue is one of the two outermost positively charged residues of the potassium channel's S4 voltage sensor (PMID: 31177578). In vitro studies of CHO cells expressing KCNQ3 channel subunits with this variant demonstrated that it leads to a near complete loss of time-dependent channel opening kinetics and an overall increase in potassium current amplitude, indicating that this variant likely exerts a gain-of-function effect (PMID: 31177578). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/251138) and thus is presumed to be rare. The c.689G>A (p.Arg230His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.689G>A (p.Arg230His) variant is classified as Pathogenic. -

Nov 13, 2017

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Feb 12, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.689G>A (p.R230H) alteration is located in exon 4 (coding exon 4) of the KCNQ3 gene. This alteration results from a G to A substitution at nucleotide position 689, causing the arginine (R) at amino acid position 230 to be replaced by a histidine (H). for KCNQ3-related neurodevelopmental disorder. Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/251138) total alleles studied. The highest observed frequency was 0.003% (1/30614) of South Asian alleles. This variant has been reported in multiple individuals with features consistent with KCNQ3-related neurodevelopmental disorder; in at least one individual, it was determined to be de novo or the result of germline mosaicism (Sands, 2019; Ambry internal data). Other variants at the same codon, c.688C>T (p.R230C) and c.688C>A (p.R230S), have been identified in multiple individuals with features consistent with KCNQ3-related neurodevelopmental disorder (Rauch, 2012; Epi4K, 2013; Bosch, 2016; Grozeva, 2015). This amino acid position is highly conserved in available vertebrate species. The p.R230 amino acid is located in the S4 transmembrane segment of the Kv7.3 voltage-gated potassium channel, which forms the voltage sensor (Miceli, 2015). The p.R230 amino acid is the second positively charged residue in the voltage sensor; these positively charged residues serve as gating charges and respond to voltage differences across the cell membrane (Bezanilla, 2008). Alterations in this amino acid position have been shown to be deleterious in several KCNQ channels (Miceli, 2011). Structural modeling performed in house at Ambry Genetics indicates that the p.R230H is structurally deleterious. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Benign neonatal seizures Pathogenic:1

Oct 23, 2024

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 histidine, which is basic and polar, at codon 230 of the KCNQ3 protein (p.Arg230His). This variant is present in population databases (rs749205120, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant KCNQ3-related disease (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 424397). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 30578330). This variant disrupts the p.Arg230 amino acid residue in KCNQ3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23020937, 23934111, 25740509, 30578330). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1

Dec 14, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS1,PS4,PM2,PM6,PP2,PP3 -

Seizure Pathogenic:1

Oct 09, 2024

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.7	D;.;D;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.018	D;.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;.
Polyphen		1.0	D;.;.;D;.
Vest4		0.94
MutPred		0.90		Loss of MoRF binding (P = 0.0114);.;.;Loss of MoRF binding (P = 0.0114);.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.66
gMVP		0.97
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs749205120; hg19: chr8-133192492; COSMIC: COSV66465699;