NM_004519.4(KCNQ3):c.950T>C (p.Ile317Thr) AND Seizures, benign familial neonatal, 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 24, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000853346.3

Allele description [Variation Report for NM_004519.4(KCNQ3):c.950T>C (p.Ile317Thr)]

NM_004519.4(KCNQ3):c.950T>C (p.Ile317Thr)

Gene:

KCNQ3:potassium voltage-gated channel subfamily Q member 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q24.22

Genomic location:

Preferred name:

NM_004519.4(KCNQ3):c.950T>C (p.Ile317Thr)

HGVS:

NC_000008.11:g.132174333A>G
NG_008854.2:g.311425T>C
NM_001204824.2:c.590T>C
NM_004519.4:c.950T>CMANE SELECT
NP_001191753.1:p.Ile197Thr
NP_004510.1:p.Ile317Thr
NC_000008.10:g.133186580A>G
NM_004519.3:c.950T>C

Protein change:

I197T

Links:

dbSNP: rs1586800133

NCBI 1000 Genomes Browser:

rs1586800133

Molecular consequence:

NM_001204824.2:c.590T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004519.4:c.950T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Seizures, benign familial neonatal, 2
Synonyms:: CONVULSIONS, BENIGN FAMILIAL NEONATAL, 2; Seizures, benign neonatal, 2; Benign Neonatal Epilepsy 2; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007366; MedGen: C1852581; Orphanet: 1949; OMIM: 121201

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000996208	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 24, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002061349	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000996208

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 24, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002061349

GeneReviews

no classification provided

not provided

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A.

Soldovieri MV, Boutry-Kryza N, Milh M, Doummar D, Heron B, Bourel E, Ambrosino P, Miceli F, De Maria M, Dorison N, Auvin S, Echenne B, Oertel J, Riquet A, Lambert L, Gerard M, Roubergue A, Calender A, Mignot C, Taglialatela M, Lesca G.

Hum Mutat. 2014 Mar;35(3):356-67. doi: 10.1002/humu.22500. Epub 2014 Jan 13.

PubMed [citation]

PMID:: 24375629

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996208.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

This variant has been previously reported as a heterozygous change in three related individuals with neonatal seizures (all 3 tested individuals), and additionally, febrile seizures and cognitive impairment (2 out of 3 tested individuals) (PMID: 24375629). This variant is located in the S5-S6 linker, one residue upstream of the GYG sequence of the selectivity filter. In vitro functional testing of this variant using patch-clamping of transfected CHO cells demonstrated that this variant confers decreased current density (PMID: 24375629). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.950T>C (p.Ile317Thr) variant 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.950T>C (p.Ile317Thr) variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From GeneReviews, SCV002061349.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Moderate psychomotor delay in some family members

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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