ClinVar Genomic variation as it relates to human health
NM_004974.4(KCNA2):c.881G>A (p.Arg294His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004974.4(KCNA2):c.881G>A (p.Arg294His)
Variation ID: 280584 Accession: VCV000280584.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p13.3 1: 110603902 (GRCh38) [ NCBI UCSC ] 1: 111146524 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 7, 2017 May 12, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004974.4:c.881G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004965.1:p.Arg294His missense NM_001204269.1:c.881G>A NM_001204269.2:c.881G>A NP_001191198.1:p.Arg294His missense NC_000001.11:g.110603902C>T NC_000001.10:g.111146524C>T NG_027997.2:g.32573G>A - Protein change
- R294H
- Other names
- p.R294H
- Canonical SPDI
- NC_000001.11:110603901:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- loss_of_function_variant Sequence Ontology [SO:0002054]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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KCNA2 | - | - |
GRCh38 GRCh37 |
458 | 480 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000339475.31 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 16, 2020 | RCV000622695.8 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000706154.18 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446499.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Spastic paraplegia (present) , Dysarthria (present) , Cerebellar ataxia (present) , Paraparesis (present) , Gait disturbance (present)
Sex: female
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Pathogenic
(Jan 04, 2021)
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criteria provided, single submitter
Method: research
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Developmental and epileptic encephalopathy, 32
Affected status: yes
Allele origin:
unknown
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Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519146.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
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Pathogenic
(Jun 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 32
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV001827221.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Both GOF and LOF variants have been described in KCNA2. This patient has a known LOF variant associated with spasticity, autism like features, and very … (more)
Both GOF and LOF variants have been described in KCNA2. This patient has a known LOF variant associated with spasticity, autism like features, and very mild developmental delay. The onset of spasticity associated with KCNA2 variants has ranged from 2-20 years of age. Clinical seizures are uncommon with LOF variants, but epileptiform discharges have been observed more frequently. (less)
Number of individuals with the variant: 1
Clinical Features:
Attention deficit hyperactivity disorder (present) , Seizure (present) , Cerebellar ataxia (present) , Spasticity (present) , Abnormal cerebellum morphology (present) , Cerebellar atrophy (present) , … (more)
Attention deficit hyperactivity disorder (present) , Seizure (present) , Cerebellar ataxia (present) , Spasticity (present) , Abnormal cerebellum morphology (present) , Cerebellar atrophy (present) , Syringomyelia (present) (less)
Age: 20-29 years
Sex: male
Ethnicity/Population group: Causasians
Tissue: blood
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Likely pathogenic
(Sep 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002064334.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Pathogenic
(Feb 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000330512.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: significantly reduced current amplitudes in X. laevis oocytes, with a dominant-negative effect observed when co-expressed with wild type … (more)
Published functional studies demonstrate a damaging effect: significantly reduced current amplitudes in X. laevis oocytes, with a dominant-negative effect observed when co-expressed with wild type (Helgib et al., 2016; Manole et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27543892, 28032718, 27513193, 33802230, 34445196) (less)
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Likely pathogenic
(Sep 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 32
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934289.3
First in ClinVar: Sep 25, 2021 Last updated: Sep 09, 2023 |
Comment:
Criteria applied: PS4_MOD,PS3_SUP,PM2_SUP,PP2,PP3
Clinical Features:
Intellectual disability (present) , Failure to thrive in infancy (present) , Febrile seizure (within the age range of 3 months to 6 years) (present) , … (more)
Intellectual disability (present) , Failure to thrive in infancy (present) , Febrile seizure (within the age range of 3 months to 6 years) (present) , Focal-onset seizure (present) , Infantile muscular hypotonia (present) , Tremor (present) , Global developmental delay (present) , Microcephaly (present) , Axial hypotonia (present) , Seizure (present) (less)
Sex: male
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 32
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000835190.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 294 of the KCNA2 protein (p.Arg294His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 294 of the KCNA2 protein (p.Arg294His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant spastic paraplegia, ataxia, intellectual disability and/or epilepsy (PMID: 27543892, 28032718, 33802230). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 280584). 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 expected to disrupt KCNA2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNA2 function (PMID: 27543892, 28032718). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000740702.5
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.881G>A (p.R294H) alteration is located in exon 3 (coding exon 1) of the KCNA2 gene. This alteration results from a G to A substitution … (more)
The c.881G>A (p.R294H) alteration is located in exon 3 (coding exon 1) of the KCNA2 gene. This alteration results from a G to A substitution at nucleotide position 881, causing the arginine (R) at amino acid position 294 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the KCNA2 c.881G>A alteration was not observed, with coverage at this position. The KCNA2 c.881G>A (p.R294H) alteration has been reported in six individuals from three unrelated families with hereditary spastic paraplegia (Helbig, 2016; Manole, 2017). In one patient, the alteration was confirmed de novo. A seventh patient was reported with the de novo c.881G>A (p.R294H) alteration, who had ataxia and intellectual disability; she exhibited no signs of spasticity at age 20 years (Helbig, 2016). She also had early onset absence epilepsy, which may be unrelated to the KCNA2 alteration. The p.R294 amino acid is completely conserved in available vertebrate species. The p.R294 amino acid is located in the S4 transmembrane segment of the Kv1.2 channel, which forms the voltage sensor domain (Tombola, 2005; Delemotte, 2010). This arginine is the first of six evenly spaced and highly conserved positively charged amino acid residues (p.R294, p.R297, p.R300, p.R303, p.K306, p.R309), which act as "gating charges" and respond to a voltage difference across the cell membrane, allowing Kv1.2 to assume either an open or closed conformation that allows potassium ions to flow through the channel based on their electrochemical gradient (Seoh, 1996; Aggarwal, 1996; Long, 2005). Functional analysis of the p.R294H alteration in Xenopus oocytes revealed that the variant results in a loss of channel function with a dominant-negative effect (Helbig, 2016; Manole, 2017). The p.R294H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000493332.28
First in ClinVar: Dec 06, 2016 Last updated: May 12, 2024 |
Comment:
KCNA2: PS4, PM2, PM6, PP2, PP3, PS3:Supporting
Number of individuals with the variant: 4
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Pathogenic
(Sep 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 32
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764742.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Spastic tetraparesis (present) , Sensorimotor neuropathy (present)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035677.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037553.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders. | Döring JH | International journal of molecular sciences | 2021 | PMID: 33802230 |
De novo KCNA2 mutations cause hereditary spastic paraplegia. | Manole A | Annals of neurology | 2017 | PMID: 28032718 |
Effect of sensor domain mutations on the properties of voltage-gated ion channels: molecular dynamics studies of the potassium channel Kv1.2. | Delemotte L | Biophysical journal | 2010 | PMID: 21044565 |
Voltage sensor of Kv1.2: structural basis of electromechanical coupling. | Long SB | Science (New York, N.Y.) | 2005 | PMID: 16002579 |
Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores. | Tombola F | Neuron | 2005 | PMID: 15694325 |
Contribution of the S4 segment to gating charge in the Shaker K+ channel. | Aggarwal SK | Neuron | 1996 | PMID: 8663993 |
Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel. | Seoh SA | Neuron | 1996 | PMID: 8663992 |
Text-mined citations for rs886041761 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.