rs104894355

Positions:

• chr12-4912588-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000217.3(KCNA1):​c.1210G>A​(p.Val404Ile) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: KCNA1 NM_000217.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 10.0

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]

ENSG00000256654 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNA1. . Gene score misZ 3.3255 (greater than the threshold 3.09). Trascript score misZ 3.8671 (greater than threshold 3.09). GenCC has associacion of gene with episodic kinesigenic dyskinesia 1, episodic ataxia type 1, developmental and epileptic encephalopathy, isolated autosomal dominant hypomagnesemia, Glaudemans type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 12-4912588-G-A is Pathogenic according to our data. Variant chr12-4912588-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA1	NM_000217.3	c.1210G>A	p.Val404Ile	missense_variant	2/2	ENST00000382545.5	NP_000208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA1	ENST00000382545.5	c.1210G>A	p.Val404Ile	missense_variant	2/2	4	NM_000217.3	ENSP00000371985.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 404 of the KCNA1 protein (p.Val404Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with episodic ataxia (PMID: 9600245, 25659636; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13487). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCNA1 function (PMID: 21307345, 25659636). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 27, 2020	The KCNA1 c.1210G>A variant is classified as PATHOGENIC (PM2, PP3, PS3, PS4) The KCNA1 c.1210G>A variant is a single nucleotide change in exon 2 of the KCNA1 gene, which is predicted to change the amino acid valine at position 404 in the protein to isoleucine. This variant has been reported in multiple patients with Episodic ataxia type I (PMID:28216637, 25659636, 9600245) (PS4). This variant is in dbSNP (rs104894355) but is absent from population databases (PM2). This variant has been reported in ClinVar as Pathogenic (Variation ID: 13487) and in HGMD as damaging (CM981109) for Episodic ataxia. Functional studies have shown a decreased infinity for the inactivation domain, slowing down inactivation of potassium channels (PMID: 21307345) (PS3). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest this variant may have a mildly damaging effect on channel function, however some measures of channel functionality were not statistically significant (Eunson et al., 2000; Imbrici et al., 2011; Ferrick-Kiddie et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11026449, 26944241, 33144682, 17156368, 9600245, 25659636, 11773313, 21307345, 28216637) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.89	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.74		Gain of catalytic residue at L402 (P = 3e-04);
MVP		0.98
MPC		2.2
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.65
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894355; hg19: chr12-5021754; COSMIC: COSV66837628;