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NM_198503.5(KCNT2):c.1619C>T (p.Pro540Leu) AND Developmental and epileptic encephalopathy, 57

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jul 17, 2023
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:
RCV004594724.1

Allele description [Variation Report for NM_198503.5(KCNT2):c.1619C>T (p.Pro540Leu)]

NM_198503.5(KCNT2):c.1619C>T (p.Pro540Leu)

Gene:
KCNT2:potassium sodium-activated channel subfamily T member 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q31.3
Genomic location:
Preferred name:
NM_198503.5(KCNT2):c.1619C>T (p.Pro540Leu)
HGVS:
  • NC_000001.11:g.196340505G>A
  • NM_001287819.3:c.1619C>T
  • NM_001287820.3:c.1469C>T
  • NM_198503.5:c.1619C>TMANE SELECT
  • NP_001274748.1:p.Pro540Leu
  • NP_001274749.1:p.Pro490Leu
  • NP_940905.2:p.Pro540Leu
  • NC_000001.10:g.196309635G>A
  • NM_198503.4:c.1619C>T
  • NR_146057.2:n.1641C>T
  • NR_146058.2:n.1750C>T
Protein change:
P490L
Molecular consequence:
  • NM_001287819.3:c.1619C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001287820.3:c.1469C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198503.5:c.1619C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_146057.2:n.1641C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146058.2:n.1750C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Developmental and epileptic encephalopathy, 57
Synonyms:
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 57
Identifiers:
MONDO: MONDO:0033366; MedGen: C4540411; OMIM: 617771

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005086172Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jul 17, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A De Novo Mutation in the Sodium-Activated Potassium Channel KCNT2 Alters Ion Selectivity and Causes Epileptic Encephalopathy.

Gururaj S, Palmer EE, Sheehan GD, Kandula T, Macintosh R, Ying K, Morris P, Tao J, Dias KR, Zhu Y, Dinger ME, Cowley MJ, Kirk EP, Roscioli T, Sachdev R, Duffey ME, Bye A, Bhattacharjee A.

Cell Rep. 2017 Oct 24;21(4):926-933. doi: 10.1016/j.celrep.2017.09.088.

PubMed [citation]
PMID:
29069600
PMCID:
PMC5687820

De novo gain-of-function variants in KCNT2 as a novel cause of developmental and epileptic encephalopathy.

Ambrosino P, Soldovieri MV, Bast T, Turnpenny PD, Uhrig S, Biskup S, Döcker M, Fleck T, Mosca I, Manocchio L, Iraci N, Taglialatela M, Lemke JR.

Ann Neurol. 2018 Jun;83(6):1198-1204. doi: 10.1002/ana.25248.

PubMed [citation]
PMID:
29740868
See all PubMed Citations (4)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086172.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Both loss of function and gain of function are known mechanisms of disease for this gene. Gain of function, loss of function, change of function, and the possibility of a dominant negative mechanism, have all been reported for pathogenic KCNT2 variants in patients with early-onset epileptic encephalopathies, including epilepsy of infancy with migrating focal seizures (PMIDs: 29069600, 29740868, 32038177). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Aug 4, 2024