ClinVar Genomic variation as it relates to human health
NM_172107.4(KCNQ2):c.365C>T (p.Ser122Leu)
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_172107.4(KCNQ2):c.365C>T (p.Ser122Leu)
Variation ID: 21787 Accession: VCV000021787.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.33 20: 63446769 (GRCh38) [ NCBI UCSC ] 20: 62078122 (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 Jan 19, 2017 Feb 14, 2024 Jan 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172107.4:c.365C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_742105.1:p.Ser122Leu missense NM_004518.6:c.365C>T NP_004509.2:p.Ser122Leu missense NM_172106.3:c.365C>T NP_742104.1:p.Ser122Leu missense NM_172108.5:c.365C>T NP_742106.1:p.Ser122Leu missense NM_172109.3:c.365C>T NP_742107.1:p.Ser122Leu missense NC_000020.11:g.63446769G>A NC_000020.10:g.62078122G>A NG_009004.2:g.30872C>T - Protein change
- S122L
- Other names
- p.S122L:TCG>TTG
- Canonical SPDI
- NC_000020.11:63446768: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
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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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KCNQ2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
2095 | 2214 |
Conditions - Germline
Condition
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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
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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 (3) |
criteria provided, single submitter
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Feb 16, 2022 | RCV000187851.9 | |
not provided (1) |
no classification provided
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- | RCV000678078.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 6, 2024 | RCV000692591.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763058.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 26, 2019 | RCV001270883.5 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002510564.2 |
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
(Jun 26, 2019)
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criteria provided, single submitter
Method: clinical testing
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KCNQ2-Related Disorders
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001451662.1
First in ClinVar: Dec 23, 2020 Last updated: Dec 23, 2020 |
Comment:
The KCNQ2 c.365C>T (p.Ser122Leu) variant is a missense variant that has been reported in three studies, in which it is found in a heterozygous state … (more)
The KCNQ2 c.365C>T (p.Ser122Leu) variant is a missense variant that has been reported in three studies, in which it is found in a heterozygous state in a total of six individuals, of whom three are unrelated (Hunter et al. 2006; Zhang et al. 2015; Millichap et al. 2016). One individual had early onset epileptic encephalopathy and five had benign familial neonatal seizures (BFNS). The p.Ser122Leu variant was found in a father with BNFS and his two affected sons, but was absent from three unaffected family members (Hunter et al. 2006). Additionally, a pair of siblings with BFNS were found to be heterozygous for the variant, but parental testing was not performed (Millichap et al. 2016). The variant was absent from 400 control subjects and is not found in the Genome Aggregation Database despite being in a region of good sequence coverage, so the variant is presumed to be rare. Electrophysiology studies were performed in Xenopus oocytes to assess the effect of the p.Ser122Leu variant. A shift in voltage dependence of activation was observed resulting in reduction of activation kinetics when compared to wild type (Hunter et al. 2006). Based on the collective evidence and the application of ACMG criteria, the p.Ser122Leu variant is classified as pathogenic for KCNQ2-related disorders. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 7
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820280.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
The missense variant p.S122L in KCNQ2 (NM_172107.4) has been previously reported in heterozygous state in affected indviduals with both epileptic encephalopathy and benign neonatal seizures … (more)
The missense variant p.S122L in KCNQ2 (NM_172107.4) has been previously reported in heterozygous state in affected indviduals with both epileptic encephalopathy and benign neonatal seizures (Zhang Y et al, Millichap J et al). Experimental studies show slower electrophysiological activation as compared to wild type (Hunter J et al). The variant has been deposited to ClinVar as Pathogenic. The p.S122L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.S122L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.365 in KCNQ2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic (less)
Clinical Features:
Movement disorder (present) , Global developmental delay (present)
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Seizures, benign familial neonatal, 1
Developmental and epileptic encephalopathy, 7
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893543.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Feb 16, 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: SCV000241451.16
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate slowed activation kinetics of the voltage-gated channel (Hunter et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); … (more)
Published functional studies demonstrate slowed activation kinetics of the voltage-gated channel (Hunter et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); 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 substitution is predicted to be within the extracellular loop between the S1 and S2 transmembrane segments; This variant is associated with the following publications: (PMID: 33098118, 16916607, 18238816, 28074849, 28082013, 27602407, 18698150, 28488083, 26544041, 34070668, 34711204, 33659638) (less)
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Pathogenic
(Jan 06, 2024)
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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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Invitae
Accession: SCV000820421.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 122 of the KCNQ2 protein (p.Ser122Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 122 of the KCNQ2 protein (p.Ser122Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 16916607, 26544041, 27602407). 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: 21787). 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 KCNQ2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 16916607). For these reasons, this variant has been classified as Pathogenic. (less)
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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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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808441.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932516.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Seizures, benign familial neonatal, 1
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000041639.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022
Comment:
Functional effect: Rightward shift in current voltage-dependence in the sub-threshold region; decrease in current activation kinetics
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Comment:
BFNE (benign familial neonatal epilepsy). FS (febrile seizures) in later life; seizures until 7 years.
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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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KCNQ2-Related Disorders. | Adam MP | - | 2022 | PMID: 20437616 |
KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. | Millichap JJ | Neurology. Genetics | 2016 | PMID: 27602407 |
Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. | Zhang Y | PloS one | 2015 | PMID: 26544041 |
Subthreshold changes of voltage-dependent activation of the K(V)7.2 channel in neonatal epilepsy. | Hunter J | Neurobiology of disease | 2006 | PMID: 16916607 |
Text-mined citations for rs118192194 ...
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.