NM_004974.4(KCNA2):c.1214C>T (p.Pro405Leu) AND Developmental and epileptic encephalopathy, 32

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Mar 14, 2024
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:: RCV000170511.24

Allele description [Variation Report for NM_004974.4(KCNA2):c.1214C>T (p.Pro405Leu)]

NM_004974.4(KCNA2):c.1214C>T (p.Pro405Leu)

Gene:

KCNA2:potassium voltage-gated channel subfamily A member 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p13.3

Genomic location:

Preferred name:

NM_004974.4(KCNA2):c.1214C>T (p.Pro405Leu)

HGVS:

NC_000001.11:g.110603569G>A
NG_027997.2:g.32906C>T
NM_001204269.2:c.894+320C>T
NM_004974.4:c.1214C>TMANE SELECT
NP_004965.1:p.Pro405Leu
NC_000001.10:g.111146191G>A
NM_004974.3:c.1214C>T
P16389:p.Pro405Leu

Protein change:

P405L; PRO405LEU

Links:

UniProtKB: P16389#VAR_073707; OMIM: 176262.0001

Molecular consequence:

NM_001204269.2:c.894+320C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_004974.4:c.1214C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Developmental and epileptic encephalopathy, 32 (DEE32)
Synonyms:: Epileptic encephalopathy, early infantile, 32
Identifiers:: MONDO: MONDO:0014607; MedGen: C4225350; Orphanet: 442835; OMIM: 616366

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000222943	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001132802	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Jan 29, 2019)	germline	clinical testing
SCV001164173	Génétique des Maladies du Développement, Hospices Civils de Lyon	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 9, 2017)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25751627, 25741868
SCV001215242	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25751627, 28492532
SCV001426145	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Apr 19, 2018)	germline	clinical testing	Citation Link,
SCV001950005	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 16, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002023206	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004801198	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2024)	germline	research	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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.

Syrbe S, Hedrich UBS, Riesch E, Djémié T, Müller S, Møller RS, Maher B, Hernandez-Hernandez L, Synofzik M, Caglayan HS, Arslan M, Serratosa JM, Nothnagel M, May P, Krause R, Löffler H, Detert K, Dorn T, Vogt H, Krämer G, Schöls L, Mullis PE, et al.

Nat Genet. 2015 Apr;47(4):393-399. doi: 10.1038/ng.3239. Epub 2015 Mar 9.

PubMed [citation]

PMID:: 25751627
PMCID:: PMC4380508

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000222943.3

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

Description

In 3 unrelated patients (patients 1, 4, and 5) with developmental and epileptic encephalopathy-32 (DEE32; 616366), Syrbe et al. (2015) identified a de novo heterozygous c.1214C-T transition (c.1214C-T, NM_004974) in the KCNA2 gene, resulting in a pro405-to-leu (P405L) substitution at a highly conserved residue in the S6 transmembrane pore domain of the channel. The mutation, which was found by whole-exome or next-generation sequencing of a targeted panel of putative epilepsy genes, was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or Exome Aggregation Consortium databases. In vitro functional expression studies in Xenopus oocytes showed that the P405L mutation caused a dramatic reduction in current amplitude in a dominant-negative manner, consistent with a loss of channel function. After normal early development, the patients had onset of seizures between 8 and 17 months of age. They became seizure-free between 4 and 15 years 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 Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001132802.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	germline	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, SCV001164173.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001215242.4

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

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 405 of the KCNA2 protein (p.Pro405Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 25751627). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190325). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNA2 protein function. Experimental studies have shown that this missense change affects KCNA2 function (PMID: 25751627). For these reasons, this variant has been classified as Pathogenic.

#	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

From Blueprint Genetics, SCV001426145.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	germline	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, SCV001950005.1

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

From Revvity Omics, Revvity, SCV002023206.3

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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004801198.2

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

#	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: Oct 20, 2024

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