NM_020822.3(KCNT1):c.2849G>A (p.Arg950Gln) AND Developmental and epileptic encephalopathy, 14

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 27, 2022
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:: RCV001004680.5

Allele description [Variation Report for NM_020822.3(KCNT1):c.2849G>A (p.Arg950Gln)]

NM_020822.3(KCNT1):c.2849G>A (p.Arg950Gln)

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.2849G>A (p.Arg950Gln)

HGVS:

NC_000009.12:g.135784031G>A
NG_033070.1:g.86847G>A
NM_001272003.2:c.2714G>A
NM_020822.3:c.2849G>AMANE SELECT
NP_001258932.1:p.Arg905Gln
NP_065873.2:p.Arg950Gln
NC_000009.11:g.138675877G>A
NM_020822.2:c.2849G>A

Protein change:

R905Q

Links:

Molecular consequence:

NM_001272003.2:c.2714G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020822.3:c.2849G>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
SCV001164136	Génétique des Maladies du Développement, Hospices Civils de Lyon	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 15, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26122718, 25741868
SCV002572898	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27029629, 26122718, 29100083, 25741868
SCV002578112	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin See additional submitters CUBI - Core Unit Bioinformatics, Berlin Institute of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001164136

Génétique des Maladies du Développement, Hospices Civils de Lyon

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 15, 2017)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002572898

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 1, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002578112

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 27, 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	germline	yes	2	not provided	not provided	2	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A targeted resequencing gene panel for focal epilepsy.

Hildebrand MS, Myers CT, Carvill GL, Regan BM, Damiano JA, Mullen SA, Newton MR, Nair U, Gazina EV, Milligan CJ, Reid CA, Petrou S, Scheffer IE, Berkovic SF, Mefford HC.

Neurology. 2016 Apr 26;86(17):1605-12. doi: 10.1212/WNL.0000000000002608. Epub 2016 Mar 30.

PubMed [citation]

PMID:: 27029629
PMCID:: PMC4844234

Mutations in KCNT1 cause a spectrum of focal epilepsies.

Møller RS, Heron SE, Larsen LH, Lim CX, Ricos MG, Bayly MA, van Kempen MJ, Klinkenberg S, Andrews I, Kelley K, Ronen GM, Callen D, McMahon JM, Yendle SC, Carvill GL, Mefford HC, Nabbout R, Poduri A, Striano P, Baglietto MG, Zara F, Smith NJ, et al.

Epilepsia. 2015 Sep;56(9):e114-20. doi: 10.1111/epi.13071. Epub 2015 Jun 30.

PubMed [citation]

PMID:: 26122718
PMCID:: PMC5915334

See all PubMed Citations (4)

Details of each submission

From Génétique des Maladies du Développement, Hospices Civils de Lyon, SCV001164136.1

#	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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002572898.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000286710). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 26122718 , 27029629 , 29100083). A different missense change at the same codon (p.Arg950Leu) has been reported to be associated with KCNT1-related disorder (ClinVar ID: VCV000473378). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	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 Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, SCV002578112.1

#	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	1	Blood	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine