NM_004974.4(KCNA2):c.1120A>G (p.Thr374Ala) AND Developmental and epileptic encephalopathy, 32

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Aug 15, 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:: RCV000677419.5

Allele description [Variation Report for NM_004974.4(KCNA2):c.1120A>G (p.Thr374Ala)]

NM_004974.4(KCNA2):c.1120A>G (p.Thr374Ala)

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.1120A>G (p.Thr374Ala)

HGVS:

NC_000001.11:g.110603663T>C
NG_027997.2:g.32812A>G
NM_001204269.2:c.894+226A>G
NM_004974.4:c.1120A>GMANE SELECT
NP_004965.1:p.Thr374Ala
NC_000001.10:g.111146285T>C
NM_004974.3:c.1120A>G

Protein change:

T374A

Links:

dbSNP: rs1553181280

NCBI 1000 Genomes Browser:

rs1553181280

Molecular consequence:

NM_001204269.2:c.894+226A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_004974.4:c.1120A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000803725	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 23, 2018)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001135388	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001438323	National Institute of Neuroscience, National Center of Neurology and Psychiatry	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 33624935
SCV003294142	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 15, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27117551, 29050392, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Whole genome sequencing of 45 Japanese patients with intellectual disability.

Abe-Hatano C, Iida A, Kosugi S, Momozawa Y, Terao C, Ishikawa K, Okubo M, Hachiya Y, Nishida H, Nakamura K, Miyata R, Murakami C, Takahashi K, Hoshino K, Sakamoto H, Ohta S, Kubota M, Takeshita E, Ishiyama A, Nakagawa E, Sasaki M, Kato M, et al.

Am J Med Genet A. 2021 May;185(5):1468-1480. doi: 10.1002/ajmg.a.62138. Epub 2021 Feb 24.

PubMed [citation]

PMID:: 33624935
PMCID:: PMC8247954

See all PubMed Citations (5)

Details of each submission

From Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV000803725.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001135388.1

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

From National Institute of Neuroscience, National Center of Neurology and Psychiatry, SCV001438323.1

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

From Invitae, SCV003294142.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects KCNA2 function (PMID: 29050392). 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. ClinVar contains an entry for this variant (Variation ID: 559647). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 27117551, 29050392). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 374 of the KCNA2 protein (p.Thr374Ala).

#	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 14, 2024

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