NM_020822.3(KCNT1):c.862G>A (p.Gly288Ser) AND multiple conditions

Clinical significance:Pathogenic (Last evaluated: Sep 9, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000627792.4

Allele description [Variation Report for NM_020822.3(KCNT1):c.862G>A (p.Gly288Ser)]

NM_020822.3(KCNT1):c.862G>A (p.Gly288Ser)

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.862G>A (p.Gly288Ser)
HGVS:
  • NC_000009.12:g.135759686G>A
  • NG_033070.1:g.62502G>A
  • NM_001272003.2:c.727G>A
  • NM_020822.3:c.862G>AMANE SELECT
  • NP_001258932.1:p.Gly243Ser
  • NP_065873.2:p.Gly288Ser
  • NC_000009.11:g.138651532G>A
  • NM_020822.2:c.862G>A
Protein change:
G243S; GLY288SER
Links:
OMIM: 608167.0010; dbSNP: rs587777264
NCBI 1000 Genomes Browser:
rs587777264
Molecular consequence:
  • NM_001272003.2:c.727G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020822.3:c.862G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Early infantile epileptic encephalopathy 14 (DEE14)
Synonyms:
DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 14
Identifiers:
MONDO: MONDO:0013989; MedGen: C3554195; Orphanet: 293181; OMIM: 614959
Name:
Epilepsy, nocturnal frontal lobe, 5 (ENFL5)
Synonyms:
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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000553815Invitaecriteria provided, single submitter
Pathogenic
(Sep 9, 2020)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy.

Arai-Ichinoi N, Uematsu M, Sato R, Suzuki T, Kudo H, Kikuchi A, Hino-Fukuyo N, Matsumoto M, Igarashi K, Haginoya K, Kure S.

Hum Genet. 2016 Jan;135(1):89-98. doi: 10.1007/s00439-015-1617-7. Epub 2015 Nov 23.

PubMed [citation]
PMID:
26597493

Mutations in KCNT1 cause a spectrum of focal epilepsies.

Møller RS, Heron SE, Larsen LH, Lim CX, Ricos MG, Bayly MA, van Kempen MJ, Klinkenberg S, Andrews I, Kelley K, Ronen GM, Callen D, McMahon JM, Yendle SC, Carvill GL, Mefford HC, Nabbout R, Poduri A, Striano P, Baglietto MG, Zara F, Smith NJ, et al.

Epilepsia. 2015 Sep;56(9):e114-20. doi: 10.1111/epi.13071. Epub 2015 Jun 30.

PubMed [citation]
PMID:
26122718
PMCID:
PMC5915334
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000553815.6

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

Description

This sequence change replaces glycine with serine at codon 288 of the KCNT1 protein (p.Gly288Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with epilepsy, most of whom displayed malignant migrating partial seizures in infancy (PMID: 24029078, 26122718, 26140313, 26597493). In several of these individuals, this variants was reported to be de novo (PMID: 24029078, 26122718, 26140313). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). However, this variant occurs in the pore region of the KCNT1 channel and computational molecular analysis suggests that it affects the structure of the channel (PMID: 24029078). These predictions have not been confirmed by published functional studies. In summary, this is a rare missense variant that is absent from the general population and reported in many individuals with disease. Therefore, it has been classified as Pathogenic.

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

Last Updated: Oct 2, 2021

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