rs1179635654

Variant names:

• chr12-4911874-G-A
• rs1179635654
• NM_000217.3:c.496G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-4911874-G-A
• chr12-4911874-G-C
• chr12-4911874-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000217.3(KCNA1):​c.496G>A​(p.Ala166Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A166P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNA1 NM_000217.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.93
• Publications: 1 publications found

Genes affected

KCNA1 (HGNC:6218): (potassium voltage-gated channel subfamily A member 1) This gene encodes a voltage-gated delayed potassium channel that is phylogenetically related to the Drosophila Shaker channel. The encoded protein has six putative transmembrane segments (S1-S6), and the loop between S5 and S6 forms the pore and contains the conserved selectivity filter motif (GYGD). The functional channel is a homotetramer. The N-terminus of the channel is associated with beta subunits that can modify the inactivation properties of the channel as well as affect expression levels. The C-terminus of the channel is complexed to a PDZ domain protein that is responsible for channel targeting. Mutations in this gene have been associated with myokymia with periodic ataxia (AEMK). [provided by RefSeq, Jul 2008]

KCNA1 Gene-Disease associations (from GenCC):

• episodic ataxia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• episodic kinesigenic dyskinesia 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated autosomal dominant hypomagnesemia, Glaudemans type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

ENSG00000256654 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000217.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCNA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 3.3255 (above the threshold of 3.09). Trascript score misZ: 3.8671 (above the threshold of 3.09). GenCC associations: The gene is linked to isolated autosomal dominant hypomagnesemia, Glaudemans type, episodic ataxia type 1, genetic developmental and epileptic encephalopathy, episodic kinesigenic dyskinesia 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000217.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA1	NM_000217.3	MANE Select	c.496G>A	p.Ala166Thr	missense	Exon 2 of 2	NP_000208.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA1	ENST00000382545.5	TSL:4 MANE Select	c.496G>A	p.Ala166Thr	missense	Exon 2 of 2	ENSP00000371985.3
	KCNA1	ENST00000639306.1	TSL:5	n.334G>A		non_coding_transcript_exon	Exon 1 of 2	ENSP00000492506.1
	ENSG00000256654	ENST00000541095.1	TSL:3	n.105+1402G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 1 Uncertain:2

Mar 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 166 of the KCNA1 protein (p.Ala166Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNA1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.

Jun 12, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as VUS-3A. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has limited previous evidence of pathogenicity in an unrelated individual(s). This variant has been classified as a VUS by a clinical laboratory in ClinVar, and reported in the literature in an individual with episodic ataxia (PMID: 38570113). Additional information: Variant is predicted to result in a missense amino acid change from alanine to threonine; This variant is heterozygous; This gene is associated with autosomal dominant disease; Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 1 heterozygote(s), 0 homozygote(s)); This variant has moderate functional evidence supporting abnormal protein function. Patch clamp studies support a loss of function effect for this variant as measured by peak current density when compared to controls (PMID: 38570113). Results from patch clamp assays are used with caution during variant classification; Another missense variant(s) comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Ala166Pro) has been classified as a VUS by clinical laboratories in ClinVar; Variant is located in the annotated S1 transmembrane domain (PMID: 32316562; NCBI); Missense variant with inconclusive in silico prediction and uninformative conservation; Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with episodic ataxia/myokymia syndrome (MIM#160120) (PMID: 11026449); The condition associated with this gene has incomplete penetrance (PMID: 20301785); Variants in this gene are known to have variable expressivity. Significant inter- and intra-familial variability is known for this gene, including some individuals reported to have isolated epileptic encephalopathies (PMIDs: 20301785, 32316562); Inheritance information for this variant is not currently available in this individual.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.37		Gain of catalytic residue at A170 (P = 0.0062)
MVP		0.91
MPC		2.3
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		0.014	Neutral
Varity_R		0.92
gMVP		0.95
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1179635654; hg19: chr12-5021040; COSMIC: COSV101230293; COSMIC: COSV101230293;