NM_000217.3(KCNA1):c.19G>A (p.Glu7Lys) AND Episodic ataxia type 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 20, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001113419.9

Allele description [Variation Report for NM_000217.3(KCNA1):c.19G>A (p.Glu7Lys)]

NM_000217.3(KCNA1):c.19G>A (p.Glu7Lys)

Genes:

LOC130007218:ATAC-STARR-seq lymphoblastoid silent region 4155 [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.19G>A (p.Glu7Lys)

HGVS:

NC_000012.12:g.4911397G>A
NG_011815.1:g.6491G>A
NM_000217.3:c.19G>AMANE SELECT
NP_000208.2:p.Glu7Lys
LRG_1297t1:c.19G>A
LRG_1297:g.6491G>A
LRG_1297p1:p.Glu7Lys
NC_000012.11:g.5020563G>A
NC_000012.11:g.5020563G>A
NM_000217.2:c.19G>A

Protein change:

E7K

Links:

dbSNP: rs529968149

NCBI 1000 Genomes Browser:

rs529968149

Molecular consequence:

NM_000217.3:c.19G>A - 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

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PREDICTED: Rattus norvegicus kinesin family member 16B (Kif16b), transcript vari...
PREDICTED: Rattus norvegicus kinesin family member 16B (Kif16b), transcript variant X2, mRNA
gi|2678929566|ref|XM_006235108.5|

Nucleotide
Yersinia phage vB_YenM_201.16, complete genome
Yersinia phage vB_YenM_201.16, complete genome
gi|2206602828|gb|OM046628.1|

Nucleotide
LOC123620099 [Homo sapiens]
LOC123620099 [Homo sapiens]
Gene ID:123620099

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001271192	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV002191261	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001271192

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV002191261

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 20, 2023)

germline

clinical testing

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

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

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 Illumina Laboratory Services, Illumina, SCV001271192.1

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002191261.3

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 KCNA1 protein function. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 7 of the KCNA1 protein (p.Glu7Lys). This variant is present in population databases (rs529968149, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with KCNA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 883202).

#	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: Jun 29, 2024

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