The R365X nonsense variant in the KCNQ2 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R365X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although this pathogenic variant has not been reported previously to our knowledge, its presence is consistent with the diagnosis of a KCNQ2-related disorder in this individual.
ClinVar Genomic variation as it relates to human health
NM_172107.4(KCNQ2):c.1093C>T (p.Arg365Ter)
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.
(5)
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
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_172107.4(KCNQ2):c.1093C>T (p.Arg365Ter)
Variation ID: 426132 Accession: VCV000426132.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.33 20: 63433834 (GRCh38) [ NCBI UCSC ] 20: 62065187 (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 22, 2017 Aug 25, 2024 Jun 29, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_172107.4:c.1093C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_742105.1:p.Arg365Ter nonsense NM_004518.6:c.1093C>T NP_004509.2:p.Arg365Ter nonsense NM_172106.3:c.1093C>T NP_742104.1:p.Arg365Ter nonsense NM_172108.5:c.1093C>T NP_742106.1:p.Arg365Ter nonsense NM_172109.3:c.1093C>T NP_742107.1:p.Arg365Ter nonsense NC_000020.11:g.63433834G>A NC_000020.10:g.62065187G>A NG_009004.2:g.43807C>T - Protein change
- R365*
- Other names
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- Canonical SPDI
- NC_000020.11:63433833:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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
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. |
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| KCNQ2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
2148 | 2279 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jun 29, 2023 | RCV000489438.3 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 6, 2021 | RCV001004707.4 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jan 13, 2022 | RCV001070007.7 |
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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Pathogenic
(May 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000576498.4
First in ClinVar: May 22, 2017 Last updated: May 22, 2017 |
Comment:
The R365X nonsense variant in the KCNQ2 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. … (more)
The R365X nonsense variant in the KCNQ2 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R365X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although this pathogenic variant has not been reported previously to our knowledge, its presence is consistent with the diagnosis of a KCNQ2-related disorder in this individual. (less)
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Pathogenic
(Jun 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Seizures, benign familial neonatal, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001164170.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Seizures, benign familial neonatal, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767957.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with early infantile epileptic encephalopathy, 7 (EIEE) (MIM#613720) and benign neonatal seizures, 1 (MIM#121200). Missense variants have been reported with a dominant negative mechanism (OMIM, PMID 24318194) and in patients with either BNS or EEIE. Truncating variants and those predicted to undergo NMD have been reported to cause loss of function (Decipher) and are almost exclusively found in patients with BNS (PMID: 32917465). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, however, this is only reported for patients with BNS (PMID: 25959266). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (Decipher), and have been observed in patients with benign neonatal seizures (BNS) (PMID: 23360469, PMID: 32917465). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jan 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Early infantile epileptic encephalopathy with suppression bursts
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001235214.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 426132). This variant has not been … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 426132). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg365*) in the KCNQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157, 23692823, 27779742). (less)
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Pathogenic
(Jun 29, 2023)
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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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198556.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with early infantile epileptic encephalopathy, 7 (EIEE) (MIM#613720) and benign neonatal seizures, 1 (MIM#121200). Missense variants have been reported with a dominant negative mechanism (OMIM, PMID 24318194) and in patients with either BNS or EEIE. Truncating variants and those predicted to undergo NMD have been reported to cause loss of function (Decipher) and are almost exclusively found in patients with BNS (PMID: 32917465). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, however, this is only reported for patients with BNS (PMID: 25959266). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (Decipher), and have been observed in patients with benign neonatal seizures (BNS) (PMID: 23360469, PMID: 32917465). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 426132). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg365*) in the KCNQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157, 23692823, 27779742).
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 R365X nonsense variant in the KCNQ2 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R365X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although this pathogenic variant has not been reported previously to our knowledge, its presence is consistent with the diagnosis of a KCNQ2-related disorder in this individual.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with early infantile epileptic encephalopathy, 7 (EIEE) (MIM#613720) and benign neonatal seizures, 1 (MIM#121200). Missense variants have been reported with a dominant negative mechanism (OMIM, PMID 24318194) and in patients with either BNS or EEIE. Truncating variants and those predicted to undergo NMD have been reported to cause loss of function (Decipher) and are almost exclusively found in patients with BNS (PMID: 32917465). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, however, this is only reported for patients with BNS (PMID: 25959266). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (Decipher), and have been observed in patients with benign neonatal seizures (BNS) (PMID: 23360469, PMID: 32917465). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 426132). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg365*) in the KCNQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157, 23692823, 27779742).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical characteristics of KCNQ2 encephalopathy. | Kim HJ | Brain & development | 2021 | PMID: 32917465 |
| Gene mutation analysis of 175 Chinese patients with early-onset epileptic encephalopathy. | Zhang Q | Clinical genetics | 2017 | PMID: 27779742 |
| Variable clinical expression in patients with mosaicism for KCNQ2 mutations. | Milh M | American journal of medical genetics. Part A | 2015 | PMID: 25959266 |
| Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. | Orhan G | Annals of neurology | 2014 | PMID: 24318194 |
| Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2. | Milh M | Orphanet journal of rare diseases | 2013 | PMID: 23692823 |
| Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. | Zara F | Epilepsia | 2013 | PMID: 23360469 |
| KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. | Singh NA | Brain : a journal of neurology | 2003 | PMID: 14534157 |
Text-mined citations for this variant ...
HelpRecord last updated Sep 29, 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.