12-4911898-G-T

Variant names:

• chr12-4911898-G-T
• rs104894349
• NM_000217.3:c.520G>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000217.3(KCNA1):​c.520G>T​(p.Val174Phe) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V174I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNA1 NM_000217.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.93
• Publications: 12 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: Pathogenic. The variant received 17 ACMG points.

• PM1: In a transmembrane_region Helical; Name=Segment S1 (size 21) in uniprot entity KCNA1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000217.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-4911898-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 959065.
• 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, 0.891
• PP5: Variant 12-4911898-G-T is Pathogenic according to our data. Variant chr12-4911898-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA1	NM_000217.3	c.520G>T	p.Val174Phe	missense_variant	Exon 2 of 2	ENST00000382545.5	NP_000208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA1	ENST00000382545.5	c.520G>T	p.Val174Phe	missense_variant	Exon 2 of 2	4	NM_000217.3	ENSP00000371985.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 1 Pathogenic:2

Dec 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 174 of the KCNA1 protein (p.Val174Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with episodic ataxia (PMID: 2245301, 7842011; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13482). 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%. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Dec 29, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.520G>T (p.V174F) alteration is located in exon 2 (coding exon 1) of the KCNA1 gene. This alteration results from a G to T substitution at nucleotide position 520, causing the valine (V) at amino acid position 174 to be replaced by a phenylalanine (F). Based on data from the Genome Aggregation Database (gnomAD), the KCNA1 c.520G> alteration was not observed, with coverage at this position. The KCNA1 c.520G>T (p.V174F) alteration was shown to segregate with disease in a large pedigree; samples were available from 18 affected family members and 34 unaffected family members (Browne, 1994). The p.V174 amino acid is conserved in available vertebrate species. Functional analysis demonstrated when the V174F alteration was introduced in to Xenopus oocytes, no functional homomeric channels were formed; when introduced with wild-type, almost no current was produced (Adelman, 1995). In a later study, also using Xenpus oocytes, it was shown that V174F shifted the voltage dependence of activation to more positive potentials (Zerr, 1998). The p.V174F alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.56		Gain of catalytic residue at S173 (P = 0);
MVP		0.97
MPC		2.7
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		-0.040	Neutral
Varity_R		0.91
gMVP		0.96
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs104894349; hg19: chr12-5021064;