Same nucleotide change resulting in same amino acid change has been previously reported as de novoo (ClinVar ID: VCV000369770.5, PMID: 27864847, PS2). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change (p.Gly301Asp) at the same codon has been reported as pathogenic (ClinVar ID: VCV000431095.3). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.944, 3Cnet: 0.943, PP3). 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_172107.4(KCNQ2):c.901G>A (p.Gly301Ser)
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.
(10)
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_172107.4(KCNQ2):c.901G>A (p.Gly301Ser)
Variation ID: 369770 Accession: VCV000369770.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 20q13.33 20: 63439624 (GRCh38) [ NCBI UCSC ] 20: 62070977 (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 Dec 17, 2016 Jul 23, 2024 Feb 12, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_172107.4:c.901G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_742105.1:p.Gly301Ser missense NM_004518.6:c.901G>A NP_004509.2:p.Gly301Ser missense NM_172106.3:c.901G>A NP_742104.1:p.Gly301Ser missense NM_172108.5:c.901G>A NP_742106.1:p.Gly301Ser missense NM_172109.3:c.901G>A NP_742107.1:p.Gly301Ser missense NC_000020.11:g.63439624C>T NC_000020.10:g.62070977C>T NG_009004.2:g.38017G>A - Protein change
- G301S
- Other names
- -
- Canonical SPDI
- NC_000020.11:63439623: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. |
|||
| KCNQ2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
2152 | 2283 | |
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 (1) |
criteria provided, single submitter
|
Nov 16, 2016 | RCV000416958.2 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 12, 2024 | RCV000678149.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 26, 2023 | RCV001037300.9 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Dec 17, 2022 | RCV001702362.6 |
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
(Nov 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Epileptic encephalopathy
Affected status: yes
Allele origin:
de novo
|
Neurogenetics Laboratory - MEYER, AOU Meyer
Accession: SCV000494520.1
First in ClinVar: Feb 12, 2017 Last updated: Feb 12, 2017 |
Family history: no
|
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 7
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002011952.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo (ClinVar ID: VCV000369770.5, PMID: 27864847, PS2). The missense variant … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo (ClinVar ID: VCV000369770.5, PMID: 27864847, PS2). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change (p.Gly301Asp) at the same codon has been reported as pathogenic (ClinVar ID: VCV000431095.3). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.944, 3Cnet: 0.943, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Seizure (present) , Dystonic disorder (present) , Motor stereotypies (present) , Delayed speech and language development (present) , Myopia (present) , Intellectual disability (present) , … (more)
Seizure (present) , Dystonic disorder (present) , Motor stereotypies (present) , Delayed speech and language development (present) , Myopia (present) , Intellectual disability (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Intellectual disability (present) , Generalized hypotonia (present) (less)
|
|
|
Pathogenic
(Dec 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818137.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 7
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV000807301.3
First in ClinVar: Sep 01, 2018 Last updated: Mar 18, 2023 |
|
|
|
Pathogenic
(Mar 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Early infantile epileptic encephalopathy with suppression bursts
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001200709.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 369770). This missense change has been observed in individual(s) with KCNQ2-related epilepsy (PMID: 27864847, 31418850). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 301 of the KCNQ2 protein (p.Gly301Ser). (less)
|
|
|
Pathogenic
(Feb 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 7
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004698104.2
First in ClinVar: Mar 10, 2024 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PS2,PS4,PM5_STR,PM1,PM2_SUP,PP3
Clinical Features:
Seizure (present) , Epileptic encephalopathy (present) , Hypsarrhythmia (present)
Sex: female
|
|
|
Pathogenic
(Oct 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 7
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV003921971.2
First in ClinVar: May 06, 2023 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, 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_v1.3.3, 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 (EEIE) (MIM#613720) (PMID: 24318194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two alternative missense changes (p.Gly301Ser, p.Gly301Val) have been reported as pathogenic, likely pathogenic and as a VUS (ClinVar, LOVD). One report notes the patient was de novo. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, and has been observed in several de novo patients with EEIE (ClinVar, LOVD, PMID 25959266). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929286.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001958372.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Developmental and epileptic encephalopathy, 7
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000484592.2
First in ClinVar: Dec 17, 2016 Last updated: Oct 01, 2022 |
Comment:
EE (epileptic encephalopathy)
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 369770). This missense change has been observed in individual(s) with KCNQ2-related epilepsy (PMID: 27864847, 31418850). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 301 of the KCNQ2 protein (p.Gly301Ser).
Comment:
Criteria applied: PS2,PS4,PM5_STR,PM1,PM2_SUP,PP3
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, 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 (EEIE) (MIM#613720) (PMID: 24318194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two alternative missense changes (p.Gly301Ser, p.Gly301Val) have been reported as pathogenic, likely pathogenic and as a VUS (ClinVar, LOVD). One report notes the patient was de novo. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, and has been observed in several de novo patients with EEIE (ClinVar, LOVD, PMID 25959266). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
EE (epileptic encephalopathy)
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:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo (ClinVar ID: VCV000369770.5, PMID: 27864847, PS2). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change (p.Gly301Asp) at the same codon has been reported as pathogenic (ClinVar ID: VCV000431095.3). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.944, 3Cnet: 0.943, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 369770). This missense change has been observed in individual(s) with KCNQ2-related epilepsy (PMID: 27864847, 31418850). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 301 of the KCNQ2 protein (p.Gly301Ser).
Comment:
Criteria applied: PS2,PS4,PM5_STR,PM1,PM2_SUP,PP3
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, 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 (EEIE) (MIM#613720) (PMID: 24318194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two alternative missense changes (p.Gly301Ser, p.Gly301Val) have been reported as pathogenic, likely pathogenic and as a VUS (ClinVar, LOVD). One report notes the patient was de novo. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, and has been observed in several de novo patients with EEIE (ClinVar, LOVD, PMID 25959266). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
EE (epileptic encephalopathy)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| KCNQ2-Related Disorders. | Adam MP | - | 2022 | PMID: 20437616 |
| Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy. | Goto A | Epilepsia | 2019 | PMID: 31418850 |
| Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. | Parrini E | Human mutation | 2017 | PMID: 27864847 |
| 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 |
Text-mined citations for rs1057516099 ...
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 Nov 10, 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.