ClinVar Genomic variation as it relates to human health
NM_004975.4(KCNB1):c.934C>T (p.Arg312Cys)
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_004975.4(KCNB1):c.934C>T (p.Arg312Cys)
Variation ID: 265207 Accession: VCV000265207.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.13 20: 49374626 (GRCh38) [ NCBI UCSC ] 20: 47991163 (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 Oct 10, 2016 Feb 14, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004975.4:c.934C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004966.1:p.Arg312Cys missense NC_000020.11:g.49374626G>A NC_000020.10:g.47991163G>A NG_041781.2:g.113019C>T - Protein change
- R312C
- Other names
- -
- Canonical SPDI
- NC_000020.11:49374625:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Severe decrease in peak current Functional Epilepsy Nomenclature for Ion Channels [FENICS-0087]
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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
Help
The frequency of the allele represented by this VCV record.
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- 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 | ||
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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
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. |
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KCNB1 | - | - |
GRCh38 GRCh37 |
708 | 723 |
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. |
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Pathogenic (4) |
criteria provided, single submitter
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Feb 2, 2022 | RCV000255550.7 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 16, 2024 | RCV000528443.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2019 | RCV000782147.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 7, 2017 | RCV001267282.5 |
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. |
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Likely pathogenic
(May 28, 2018)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 26
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV000890019.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
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Pathogenic
(Mar 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
de novo
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Laboratoire de Génétique Moléculaire Institut de Recherche Necker Enfants Malades, CHU Paris - Hôpital Necker-Enfants Malades
Accession: SCV000920611.1
First in ClinVar: Jun 09, 2019 Last updated: Jun 09, 2019 |
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Likely pathogenic
(Dec 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV001445463.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian/German/Polish/Irish/Dutch
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Pathogenic
(Feb 02, 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: SCV000321795.9
First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate reduction in channel conductance (Kang et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious … (more)
Published functional studies demonstrate reduction in channel conductance (Kang et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31618753, 31513310, 31600826, 32954514, 34915430, 31785789) (less)
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Pathogenic
(May 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 26
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000655445.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 312 of the KCNB1 protein … (more)
This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 312 of the KCNB1 protein (p.Arg312Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant has been observed de novo in families with KCNB1-related disease (Invitae). In at least one family the variant was inherited from an unaffected parent who was apparently germline mosaic (Invitae). ClinVar contains an entry for this variant (Variation ID: 265207). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. (less)
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Pathogenic
(Jul 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 26
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004027683.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Criteria applied: PS2,PM1,PM5,PM2_SUP,PP3
Clinical Features:
Moderate global developmental delay (present) , Microcephaly (present) , Epileptic encephalopathy (present) , Generalized-onset seizure (present)
Sex: female
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pathogenic
(Jan 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 26
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV004239250.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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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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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035209.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002038214.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
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not provided
(-)
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no classification provided
Method: in vitro
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not provided
Affected status: not applicable
Allele origin:
not applicable
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Kearney Laboratory, Northwestern University Feinberg School of Medicine
Accession: SCV004024587.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Method: Automated patch clamp recording
Result:
Severe decrease in peak current (FENICS-0087)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Severe decrease in peak current
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Method citation(s):
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Kearney Laboratory, Northwestern University Feinberg School of Medicine
Accession: SCV004024587.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Spectrum of K(V) 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders. | Kang SK | Annals of neurology | 2019 | PMID: 31600826 |
Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. | de Kovel CG | Molecular genetics & genomic medicine | 2016 | PMID: 27652284 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 14, 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.