12-4912055-C-G

Variant names:

• chr12-4912055-C-G
• rs28933383
• NM_000217.3:c.677C>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000217.3(KCNA1):​c.677C>G​(p.Thr226Arg) 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. T226K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNA1 NM_000217.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.85
• Publications: 36 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 19 ACMG points.

• PM1: In a transmembrane_region Helical; Name=Segment S2 (size 21) in uniprot entity KCNA1_HUMAN there are 6 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 chr12-4912055-C-A is described in CliVar as Pathogenic. Clinvar id is 13493.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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, 0.976
• PP5: Variant 12-4912055-C-G is Pathogenic according to our data. Variant chr12-4912055-C-G is described in CliVar as Pathogenic. Clinvar id is 13492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-4912055-C-G is described in CliVar as Pathogenic. Clinvar id is 13492.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.677C>G	p.Thr226Arg	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.677C>G	p.Thr226Arg	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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 1 Pathogenic:2 Other:1

May 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 22, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported in patients with episodic ataxia and myokymia as a de novo heterozygous change (PMID: 26395884), and as inherited in cases with multiple similarly affected family members (PMID: 10355668, 10414318, 19779067). The clinical presentations of individuals with the p.Thr226Arg is highly variable and has included complex partial epilepsy and apneic events in infancy (PMID: 10355668). Functional studies suggest the p.Thr226Arg exerts a dominant negative effect on potassium channel function and may impair neuronal repolarization (PMID: 10355668, 10414318, 11773313). An in-vitro study of this variant in rat neurons detected no effect on neuronal excitability; however, it identified increased neurotransmitter release (PMID: 19779067). Other pathogenic variants have been observed at this amino acid residue including p.Thr226Met (PMID: 8871592) and p.Thr226Lys (PMID: 17136396, 22965560). The c.677C>G (p.Thr226Arg) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.677C>G (p.Thr226Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.677C>G (p.Thr226Arg) variant is classified as Pathogenic. -

not provided Pathogenic:2

Dec 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies indicated that T226R results in a decrease in voltage activated current and cause a dominant negative effect on potassium channel function (PMID: 10355668, 10414318); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17395136, 11773313, 10414318, 19779067, 11026449, 15351427, 10355668, 26395884) -

May 09, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM1, PM2, PM6, PS3, PS4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.81		Gain of catalytic residue at F221 (P = 2e-04);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		-0.0094	Neutral
Varity_R		0.96
gMVP		0.98
Mutation Taster		=6/94	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: rs28933383; hg19: chr12-5021221;