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NM_004974.4(KCNA2):c.1214C>T (p.Pro405Leu) AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 30, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002517634.3

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:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003745333Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jun 30, 2021) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Novel clinical manifestations in patients with KCNA2 mutations.

Sachdev M, Gaínza-Lein M, Tchapyjnikov D, Jiang YH, Loddenkemper T, Mikati MA.

Seizure. 2017 Oct;51:74-76. doi: 10.1016/j.seizure.2017.07.018. Epub 2017 Aug 5.

PubMed [citation]
PMID:
28806589
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV003745333.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The c.1214C>T (p.P405L) alteration is located in exon 3 (coding exon 1) of the KCNA2 gene. This alteration results from a C to T substitution at nucleotide position 1214, causing the proline (P) at amino acid position 405 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD), the KCNA2 c.1214C>T alteration was not observed, with coverage at this position. This alteration has been reported in multiple unrelated patients with epileptic encephalopathy and is the most common recurrent variant in KCNA2 (Syrbe, 2015; Masnada, 2017; Sachdev, 2017; Miao, 2018; Gong, 2020). This amino acid position is highly conserved in available vertebrate species. Functional characterization of the P405L alteration with a voltage-clamp oocyte testing system found a dramatic reduction of current amplitudes with a dominant negative effect (Syrbe, 2015). The p.P405L alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024