The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16501573). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.76). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013473). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_004977.3(KCNC3):c.1259G>A (p.Arg420His)
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004977.3(KCNC3):c.1259G>A (p.Arg420His)
Variation ID: 13473 Accession: VCV000013473.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.33 19: 50323694 (GRCh38) [ NCBI UCSC ] 19: 50826951 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 15, 2016 Sep 29, 2024 Jan 10, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004977.3:c.1259G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004968.2:p.Arg420His missense NM_001372305.1:c.1031G>A NP_001359234.1:p.Arg344His missense NC_000019.10:g.50323694C>T NC_000019.9:g.50826951C>T NG_008134.2:g.10684G>A LRG_668:g.10684G>A LRG_668t1:c.1259G>A LRG_668p1:p.Arg420His Q14003:p.Arg420His - Protein change
- R420H, R344H
- Other names
- -
- Canonical SPDI
- NC_000019.10:50323693:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| KCNC3 | - | - |
GRCh38 GRCh37 |
315 | 389 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2022 | RCV000014415.40 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2024 | RCV000992229.5 |
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
Help
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
Help
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
Help
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Spinocerebellar ataxia type 13
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521876.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16501573). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.76). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013473). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar ataxia (present)
|
|
|
Pathogenic
(Aug 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Spinocerebellar ataxia 13
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000595295.1
First in ClinVar: Jul 25, 2016 Last updated: Jul 25, 2016 |
|
|
|
Pathogenic
(Dec 28, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV001144324.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality (0/282352 chr). Found in at least one symptomatic patient. Predicted to have … (more)
Not found in the total gnomAD dataset, and the data is high quality (0/282352 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease in affected and unaffected individuals, but from a single family. (less)
|
|
|
Pathogenic
(Aug 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Spinocerebellar ataxia type 13
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579082.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4_MOD, PP1_MOD, PM2_SUP, PP2
|
Number of individuals with the variant: 2
Sex: female
|
|
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Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005325132.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23734863, 23912307, 18592334, 20712895, 22736459, 21543613, 22289912, 25152487, 24116147, 25756792, 28216058, 29915382, 25497598, 23215817, 37365508, 35401678, 37301203, 35902028, 37887032, 36741467, 16501573) (less)
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Spinocerebellar ataxia type 13
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004046791.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
|
|
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Pathogenic
(Dec 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004298438.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that … (more)
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters KCNC3 gene expression (PMID: 16501573). 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 KCNC3 protein function. ClinVar contains an entry for this variant (Variation ID: 13473). This missense change has been observed in individual(s) with autosomal dominant spinocerebellar ataxia (PMID: 16501573). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 420 of the KCNC3 protein (p.Arg420His). (less)
|
|
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Pathogenic
(Oct 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Spinocerebellar ataxia type 13
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002802249.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Apr 01, 2006)
|
no assertion criteria provided
Method: literature only
|
SPINOCEREBELLAR ATAXIA 13
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034664.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 15, 2016 |
Comment on evidence:
In affected members of a Filipino family with SCA13 (605259) reported by Waters et al. (2005), Waters et al. (2006) identified a heterozygous 1554G-A transition … (more)
In affected members of a Filipino family with SCA13 (605259) reported by Waters et al. (2005), Waters et al. (2006) identified a heterozygous 1554G-A transition in exon 2 of the KCNC3 gene, resulting in an arg420-to-his (R420H) substitution in transmembrane segment S4 of the protein. S4 is the main voltage-sensing element of the protein. The R420H substitution was not identified in over 400 control alleles. In vitro functional expression studies showed that the R420H mutant protein had no detectable channel activity, and coexpression with wildtype KCNC3 led to suppression of current amplitude consistent with a dominant-negative effect. Pyle et al. (2015) identified a heterozygous R420H mutation in 2 sisters of European descent (patients 7 and 8) with adult-onset SCA13. The patients were part of a large study of exome analysis of 35 patients from 22 families with ataxia. (less)
|
|
|
Pathogenic
(Aug 23, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Spinocerebellar ataxia type 13
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002011773.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
|
|
|
Pathogenic
(Jul 22, 2021)
|
no assertion criteria provided
Method: research
|
Spinocerebellar ataxia type 13
Affected status: yes
Allele origin:
unknown
|
O&I group, Department of Genetics, University Medical Center of Groningen
Accession: SCV001960830.1
First in ClinVar: Mar 22, 2022 Last updated: Mar 22, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Not found in the total gnomAD dataset, and the data is high quality (0/282352 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease in affected and unaffected individuals, but from a single family.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23734863, 23912307, 18592334, 20712895, 22736459, 21543613, 22289912, 25152487, 24116147, 25756792, 28216058, 29915382, 25497598, 23215817, 37365508, 35401678, 37301203, 35902028, 37887032, 36741467, 16501573)
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters KCNC3 gene expression (PMID: 16501573). 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 KCNC3 protein function. ClinVar contains an entry for this variant (Variation ID: 13473). This missense change has been observed in individual(s) with autosomal dominant spinocerebellar ataxia (PMID: 16501573). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 420 of the KCNC3 protein (p.Arg420His).
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. |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16501573). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.76). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013473). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Not found in the total gnomAD dataset, and the data is high quality (0/282352 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease in affected and unaffected individuals, but from a single family.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23734863, 23912307, 18592334, 20712895, 22736459, 21543613, 22289912, 25152487, 24116147, 25756792, 28216058, 29915382, 25497598, 23215817, 37365508, 35401678, 37301203, 35902028, 37887032, 36741467, 16501573)
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters KCNC3 gene expression (PMID: 16501573). 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 KCNC3 protein function. ClinVar contains an entry for this variant (Variation ID: 13473). This missense change has been observed in individual(s) with autosomal dominant spinocerebellar ataxia (PMID: 16501573). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 420 of the KCNC3 protein (p.Arg420His).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Feasibility of Follow-Up Studies and Reclassification in Spinocerebellar Ataxia Gene Variants of Unknown Significance. | Ghorbani F | Frontiers in genetics | 2022 | DOI: 10.3389/fgene.2022.782685 |
| SCA13 causes dominantly inherited non-progressive myoclonus ataxia. | Montaut S | Parkinsonism & related disorders | 2017 | PMID: 28216058 |
| Functional analysis helps to define KCNC3 mutational spectrum in Dutch ataxia cases. | Duarri A | PloS one | 2015 | PMID: 25756792 |
| Exome sequencing in undiagnosed inherited and sporadic ataxias. | Pyle A | Brain : a journal of neurology | 2015 | PMID: 25497598 |
| KCNC3(R420H), a K(+) channel mutation causative in spinocerebellar ataxia 13 displays aberrant intracellular trafficking. | Gallego-Iradi C | Neurobiology of disease | 2014 | PMID: 25152487 |
| Mutation in the kv3.3 voltage-gated potassium channel causing spinocerebellar ataxia 13 disrupts sound-localization mechanisms. | Middlebrooks JC | PloS one | 2013 | PMID: 24116147 |
| Comprehensive phenotype of the p.Arg420his allelic form of spinocerebellar ataxia type 13. | Subramony SH | Cerebellum (London, England) | 2013 | PMID: 23912307 |
| Spinocerebellar ataxia-13 Kv3.3 potassium channels: arginine-to-histidine mutations affect both functional and protein expression on the cell surface. | Zhao J | The Biochemical journal | 2013 | PMID: 23734863 |
| Mesial temporal lobe epilepsy in a patient with spinocerebellar ataxia type 13 (SCA13). | Bürk K | The International journal of neuroscience | 2013 | PMID: 23215817 |
| Oculomotor and visual axis systems sparing in spinocerebellar ataxia type 13(R420H). | Waters MF | Neurology | 2012 | PMID: 22933745 |
| Spinocerebellar ataxia type 13 mutation that is associated with disease onset in infancy disrupts axonal pathfinding during neuronal development. | Issa FA | Disease models & mechanisms | 2012 | PMID: 22736459 |
| Altered Kv3.3 channel gating in early-onset spinocerebellar ataxia type 13. | Minassian NA | The Journal of physiology | 2012 | PMID: 22289912 |
| Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish. | Issa FA | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2011 | PMID: 21543613 |
| Functional effects of spinocerebellar ataxia type 13 mutations are conserved in zebrafish Kv3.3 channels. | Mock AF | BMC neuroscience | 2010 | PMID: 20712895 |
| KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients. | Figueroa KP | Human mutation | 2010 | PMID: 19953606 |
| Sca13. | Waters MF | Cerebellum (London, England) | 2008 | PMID: 18592334 |
| Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. | Waters MF | Nature genetics | 2006 | PMID: 16501573 |
| An autosomal dominant ataxia maps to 19q13: Allelic heterogeneity of SCA13 or novel locus? | Waters MF | Neurology | 2005 | PMID: 16135769 |
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Text-mined citations for rs104894699 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 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.