NM_020822.3(KCNT1):c.1421G>A (p.Arg474His) AND Autosomal dominant nocturnal frontal lobe epilepsy 5

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: May 28, 2018
Review status:: criteria provided, conflicting classifications

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:: RCV001253027.6

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:: Autosomal dominant nocturnal frontal lobe epilepsy 5
Synonyms:: Epilepsy, nocturnal frontal lobe, 5; CILIARY DYSKINESIA, PRIMARY, 28, WITHOUT SITUS INVERSUS; CILIARY DYSKINESIA, PRIMARY, 28, WITH SITUS INVERSUS
Identifiers:: MONDO: MONDO:0014002; MedGen: C3554306; Orphanet: 98784; OMIM: 615005

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001428542	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 28, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002570033	Center of Excellence for Medical Genomics, Chulalongkorn University	no assertion criteria provided	Pathogenic (Sep 8, 2002)	de novo	research
SCV004046120	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	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

SCV001428542

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 28, 2018)

germline

clinical testing

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

SCV002570033

Center of Excellence for Medical Genomics, Chulalongkorn University

no assertion criteria provided

Pathogenic
(Sep 8, 2002)

de novo

research

SCV004046120

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

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	1	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	research

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

Details of each submission

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001428542.1

#	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 Center of Excellence for Medical Genomics, Chulalongkorn University, SCV002570033.1

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

#	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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046120.1

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

Description

This variant has been previously reported as a de novo change in patients with malignant migrating partial seizures in infancy with and without systemic pulmonary collateral arteries (MMPSI) (PMID: 23086397, 28987752), malignant migrating focal seizures in infancy (PMID: 27779742), epilepsy of infancy with migrating focal seizures (EIMFS) (PMID: 31872048, 31532509, 32167590, 32505479) and sleep-related hypermotor epilepsy (PMID: 32167590). Overexpression studies demonstrated that this variant leads to increased Kcnt1 current amplitude (PMID: 25482562). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1421G>A (p.Arg474His) 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.1421G>A (p.Arg474His) variant is classified as 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

Last Updated: Jun 9, 2024

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