NM_020822.3(KCNT1):c.1421G>A (p.Arg474His) AND Developmental and epileptic encephalopathy, 14

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Mar 19, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000032795.19

Allele description [Variation Report for NM_020822.3(KCNT1):c.1421G>A (p.Arg474His)]

NM_020822.3(KCNT1):c.1421G>A (p.Arg474His)

Gene:

KCNT1:potassium sodium-activated channel subfamily T member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.3

Genomic location:

Preferred name:

NM_020822.3(KCNT1):c.1421G>A (p.Arg474His)

HGVS:

NC_000009.12:g.135768848G>A
NG_033070.1:g.71664G>A
NM_001272003.2:c.1286G>A
NM_020822.3:c.1421G>AMANE SELECT
NP_001258932.1:p.Arg429His
NP_065873.2:p.Arg474His
NC_000009.11:g.138660694G>A
NM_001272003.1:c.1286G>A
NM_020822.2:c.1421G>A

Protein change:

R429H; ARG474HIS

Links:

OMIM: 608167.0003

Molecular consequence:

NM_001272003.2:c.1286G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020822.3:c.1421G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Developmental and epileptic encephalopathy, 14 (DEE14)
Synonyms:: Early infantile epileptic encephalopathy 14
Identifiers:: MONDO: MONDO:0013989; MedGen: C3554195; Orphanet: 293181; OMIM: 614959

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000056563	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2012)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000255509	UCLA Clinical Genomics Center, UCLA - CES	criteria provided, single submitter (Lee et al. (JAMA. 2014))	Pathogenic (Feb 4, 2014)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000807326	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 19, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 25326635
SCV000928394	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 3, 2018)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001164145	Génétique des Maladies du Développement, Hospices Civils de Lyon	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2017)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23086397, 25741868
SCV001429527	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 21, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001712189	Pediatric Genetics Clinic, Sheba Medical Center	no assertion criteria provided	Pathogenic (May 13, 2021)	de novo	clinical testing
SCV002820286	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003807651	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 25, 2022)	germline	clinical testing	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	de novo	yes	2	not provided	not provided	2	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
European Caucasian,Ashkenazi Jews	de novo	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Clinical exome sequencing for genetic identification of rare Mendelian disorders.

Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M, Fox M, Fogel BL, Martinez-Agosto JA, Wong DA, Chang VY, Shieh PB, Palmer CG, Dipple KM, Grody WW, Vilain E, Nelson SF.

JAMA. 2014 Nov 12;312(18):1880-7. doi: 10.1001/jama.2014.14604.

PubMed [citation]

PMID:: 25326637
PMCID:: PMC4278636

Molecular findings among patients referred for clinical whole-exome sequencing.

Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, et al.

JAMA. 2014 Nov 12;312(18):1870-9. doi: 10.1001/jama.2014.14601.

PubMed [citation]

PMID:: 25326635
PMCID:: PMC4326249

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000056563.4

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

Description

In a 6-month-old boy (patient 5) of French origin with developmental and epileptic encephalopathy-14 (DEE14; 614959) manifest clinically as MMPSI, Barcia et al. (2012) identified a de novo heterozygous 1421G-A transition in exon 15 of the KCNT1 gene, resulting in an arg474-to-his (R474H) substitution at a highly conserved residue. The patient had onset of seizures at 2 weeks of age.

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

From UCLA Clinical Genomics Center, UCLA - CES, SCV000255509.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)
2	European Caucasian,Ashkenazi Jews	1	not provided	not provided	clinical testing	PubMed (1)

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

From Baylor Genetics, SCV000807326.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV000928394.1

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

Description

PS3, PM2, PM5, PP3

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

From Génétique des Maladies du Développement, Hospices Civils de Lyon, SCV001164145.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429527.1

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

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

From Pediatric Genetics Clinic, Sheba Medical Center, SCV001712189.1

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

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV002820286.1

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

Description

The missense variant p.R474H in KCNT1 (NM_020822.3) has been previously reported as a de novo variant in individuals with malignant migrating partial seizures of infancy (MMPSI) and West syndrome (Lee et al 2014; Barcia et al 2012; Ohba et al 2015). A different missense variant at the same position (R474C) has been reported as a pathogenic variant in individuals with epilepsy of infancy with migrating focal seizures (EIFMS) (Ohba et al, 2015). The variant has been submitted to ClinVar as Pathogenic. The p.R474H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R474H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 474 of KCNT1 is conserved in all mammalian species. The nucleotide c.1421 in KCNT1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

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

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807651.1

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

Description

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

#	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

Last Updated: Nov 30, 2024

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