NM_020822.3(KCNT1):c.862G>A (p.Gly288Ser) AND Epilepsy, nocturnal frontal lobe, 5

Clinical significance:Pathogenic (Last evaluated: Dec 4, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001265540.1

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:
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
SCV001443687Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diegocriteria provided, single submitter
Pathogenic
(Dec 4, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical 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

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001443687.1

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

Description

This variant is a recurrent gain of function alteration at a CG dinucleotide sequence in the pore region of the KCNT1 channel. The c.862G>A variant has been reported either as a de novo change or with unknown inheritance in several children with typical migrating malignant partial seizures in infancy (MMPSI) (PMID: 24029078, 26122718, 26140313, 30185235, 26993267, 25482562). Severe delayed myelination was reported in three of these patients (PMID: 26597493, 25482562). Two of these children had seizures that were initially resistant to different drugs, and responded to vagus nerve stimulation or clorazepate (PMID: 24029078). The c.862G>A, p.Gly288Ser variant was also identified in a child with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (PMID: 25482562). Other KCNT1 missense variants, including a recurrent c.1283G>A alteration identified in three sporadic cases, are located at CG dinucleotides, suggesting that the CpG dinucleotide at these various KCNT1 positions, may be hot spots for point mutations. Functional characterization of the c.862G>A, p.Gly288Ser alteration using heterologous systems showed an increased KCNT1 current (PMID: 26784557, 25482562). The c.862G>A, p.Gly288Ser is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In addition, it affects a highly conserved amino acid and is predicted to have a deleterious effect on protein function by the majority of in silico tools used for the analysis. The c.862G>A, p.Gly288Ser variant is reported in ClinVar (Variation ID: 126421). Based on the available evidence, the c.862G>A, p.Gly288Ser variant is classified as Pathogenic.

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

Last Updated: Oct 2, 2021

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