NM_020822.3(KCNT1):c.1225C>T (p.Pro409Ser) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 4, 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:: RCV000820357.6

Allele description [Variation Report for NM_020822.3(KCNT1):c.1225C>T (p.Pro409Ser)]

NM_020822.3(KCNT1):c.1225C>T (p.Pro409Ser)

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.1225C>T (p.Pro409Ser)

HGVS:

NC_000009.12:g.135765648C>T
NG_033070.1:g.68464C>T
NM_001272003.2:c.1090C>T
NM_020822.3:c.1225C>TMANE SELECT
NP_001258932.1:p.Pro364Ser
NP_065873.2:p.Pro409Ser
NC_000009.11:g.138657494C>T
NM_020822.2:c.1225C>T

Protein change:

P364S

Links:

dbSNP: rs1588344733

NCBI 1000 Genomes Browser:

rs1588344733

Molecular consequence:

NM_001272003.2:c.1090C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020822.3:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Developmental and epileptic encephalopathy, 14 (DEE14)
Synonyms:: Early infantile epileptic encephalopathy 14
Identifiers:: MONDO: MONDO:0013989; MedGen: C3554195; Orphanet: 293181; OMIM: 614959

Name:: Autosomal dominant nocturnal frontal lobe epilepsy 5
Synonyms:: Epilepsy, nocturnal frontal lobe, 5; CILIARY DYSKINESIA, PRIMARY, 28, WITHOUT SITUS INVERSUS; CILIARY DYSKINESIA, PRIMARY, 28, WITH SITUS INVERSUS
Identifiers:: MONDO: MONDO:0014002; MedGen: C3554306; Orphanet: 98784; OMIM: 615005

Recent activity

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Homo sapiens ADAM metallopeptidase domain 11 (ADAM11), mRNA
Homo sapiens ADAM metallopeptidase domain 11 (ADAM11), mRNA
gi|93141025|ref|NM_002390.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000961066	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 4, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26140313, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000961066

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 4, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

De novo KCNT1 mutations in early-onset epileptic encephalopathy.

Ohba C, Kato M, Takahashi N, Osaka H, Shiihara T, Tohyama J, Nabatame S, Azuma J, Fujii Y, Hara M, Tsurusawa R, Inoue T, Ogata R, Watanabe Y, Togashi N, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Saitsu H, Matsumoto N.

Epilepsia. 2015 Sep;56(9):e121-8. doi: 10.1111/epi.13072. Epub 2015 Jul 3.

PubMed [citation]

PMID:: 26140313

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000961066.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 409 of the KCNT1 protein (p.Pro409Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 26140313; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 662662). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNT1 protein function. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 5, 2024

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