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NM_020822.3(KCNT1):c.2849G>A (p.Arg950Gln) AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 26, 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:
RCV004021207.1

Allele description [Variation Report for NM_020822.3(KCNT1):c.2849G>A (p.Arg950Gln)]

NM_020822.3(KCNT1):c.2849G>A (p.Arg950Gln)

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.2849G>A (p.Arg950Gln)
HGVS:
  • NC_000009.12:g.135784031G>A
  • NG_033070.1:g.86847G>A
  • NM_001272003.2:c.2714G>A
  • NM_020822.3:c.2849G>AMANE SELECT
  • NP_001258932.1:p.Arg905Gln
  • NP_065873.2:p.Arg950Gln
  • NC_000009.11:g.138675877G>A
  • NM_020822.2:c.2849G>A
Protein change:
R905Q
Links:
Molecular consequence:
  • NM_001272003.2:c.2714G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020822.3:c.2849G>A - 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
SCV004893013Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Oct 26, 2023) 		germlineclinical testing

PubMed (9)
[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

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

A targeted resequencing gene panel for focal epilepsy.

Hildebrand MS, Myers CT, Carvill GL, Regan BM, Damiano JA, Mullen SA, Newton MR, Nair U, Gazina EV, Milligan CJ, Reid CA, Petrou S, Scheffer IE, Berkovic SF, Mefford HC.

Neurology. 2016 Apr 26;86(17):1605-12. doi: 10.1212/WNL.0000000000002608. Epub 2016 Mar 30.

PubMed [citation]
PMID:
27029629
PMCID:
PMC4844234
See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV004893013.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

The c.2849G>A (p.R950Q) alteration is located in exon 25 (coding exon 25) of the KCNT1 gene. This alteration results from a G to A substitution at nucleotide position 2849, causing the arginine (R) at amino acid position 950 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in the heterozygous state in multiple individuals with clinical features of KCNT1-related neurodevelopmental disorder and has been determined to be the result of a de novo mutation multiple individuals (Bonardi, 2021; Borlot, 2020; Costain, 2019; Dilena, 2018; Hamdan, 2017; Hildebrand, 2016; Møller, 2015). In addition, this alteration was reported to cosegregate with disease in one family (Rubboli, 2019). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies indicate this alteration leads to a shift in the half-activation voltage and support a gain-of-function impact on channel properties (Hinckley, 2023; Dilena, 2018). The in silico prediction for this alteration is inconclusive. 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: Sep 29, 2024