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NM_000217.3(KCNA1):c.1207C>T (p.Pro403Ser) AND Episodic ataxia type 1

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 29, 2024
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:
RCV003627413.2

Allele description [Variation Report for NM_000217.3(KCNA1):c.1207C>T (p.Pro403Ser)]

NM_000217.3(KCNA1):c.1207C>T (p.Pro403Ser)

Gene:
KCNA1:potassium voltage-gated channel subfamily A member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12p13.32
Genomic location:
Preferred name:
NM_000217.3(KCNA1):c.1207C>T (p.Pro403Ser)
HGVS:
  • NC_000012.12:g.4912585C>T
  • NG_011815.1:g.7679C>T
  • NM_000217.3:c.1207C>TMANE SELECT
  • NP_000208.2:p.Pro403Ser
  • LRG_1297t1:c.1207C>T
  • LRG_1297:g.7679C>T
  • LRG_1297p1:p.Pro403Ser
  • NC_000012.11:g.5021751C>T
Protein change:
P403S
Molecular consequence:
  • NM_000217.3:c.1207C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Episodic ataxia type 1 (EA1)
Synonyms:
ATAXIA, EPISODIC, WITH MYOKYMIA; MYOKYMIA WITH PERIODIC ATAXIA; PAROXYSMAL ATAXIA WITH NEUROMYOTONIA, HEREDITARY; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008047; MedGen: C1719788; Orphanet: 972; OMIM: 160120

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004540608Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 29, 2024) 		germlineclinical testing

PubMed (3)
[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

Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants.

Miceli F, Guerrini R, Nappi M, Soldovieri MV, Cellini E, Gurnett CA, Parmeggiani L, Mei D, Taglialatela M.

Epilepsia. 2022 Jan;63(1):e7-e14. doi: 10.1111/epi.17118. Epub 2021 Nov 14.

PubMed [citation]
PMID:
34778950
PMCID:
PMC9299230

Clinical and Functional Study of a De Novo Variant in the PVP Motif of Kv1.1 Channel Associated with Epilepsy, Developmental Delay and Ataxia.

Dinoi G, Morin M, Conte E, Mor Shaked H, Coppola MA, D'Adamo MC, Elpeleg O, Liantonio A, Hartmann I, De Luca A, Blunck R, Russo A, Imbrici P.

Int J Mol Sci. 2022 Jul 22;23(15). doi:pii: 8079. 10.3390/ijms23158079.

PubMed [citation]
PMID:
35897654
PMCID:
PMC9331732
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004540608.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 403 of the KCNA1 protein (p.Pro403Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe early onset epilepsy (PMID: 34778950). In at least one individual the variant was observed to be de novo. 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 expected to disrupt KCNA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNA1 function (PMID: 34778950). This variant disrupts the p.Pro403 amino acid residue in KCNA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 35897654). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2024