ClinVar Genomic variation as it relates to human health
NM_000744.7(CHRNA4):c.839C>T (p.Ser280Phe)
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
-
NM_000744.7(CHRNA4):c.839C>T (p.Ser280Phe)
Variation ID: 17498 Accession: VCV000017498.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 20q13.33 20: 63350572 (GRCh38) [ NCBI UCSC ] 20: 61981924 (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 May 3, 2013 Feb 14, 2024 Nov 24, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000744.7:c.839C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000735.1:p.Ser280Phe missense NM_001256573.2:c.311C>T NP_001243502.1:p.Ser104Phe missense NR_046317.2:n.1048C>T non-coding transcript variant NC_000020.11:g.63350572G>A NC_000020.10:g.61981924G>A NG_011931.1:g.15772C>T P43681:p.Ser280Phe - Protein change
- S280F, S104F
- Other names
- S252F
- Canonical SPDI
- NC_000020.11:63350571:G:A
-
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.
-
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. |
|||
CHRNA4 | - | - |
GRCh38 GRCh37 |
872 | 1129 |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 22, 2022 | RCV000019050.31 | |
Pathogenic (1) |
criteria provided, single submitter
|
Sep 11, 2015 | RCV000487099.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 24, 2023 | RCV001206285.5 |
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
(Sep 11, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000567702.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
The S280F missense change (reported as S248F due to the use of alternate nomenclature) was initially found to segregate with ADNFLE in 21 affected individuals … (more)
The S280F missense change (reported as S248F due to the use of alternate nomenclature) was initially found to segregate with ADNFLE in 21 affected individuals spanning multiple generations of a large family (Steinlein et al., 1995). It has subsequently been reported to segregate with ADNFLE in multiple other large families (Steinlein et al., 2011). The S280F variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. S280F is a non-conservative amino acid substitution that occurs at a conserved position in the second transmembrane domain of the protein, which forms the wall of the ionic pore. Functional studies in Xenopus oocytes suggest that S280F is a gain-of-function variant that results in increased sensitivity of the receptor to acetylcholine (Steinlein et al., 2011). Therefore, S280F in CHRNA4 is interpreted to be a pathogenic variant. (less)
|
|
Pathogenic
(Aug 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nocturnal frontal lobe epilepsy 1
Affected status: yes
Allele origin:
paternal
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002576430.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
_x000D_ Criteria applied: PS3, PS4, PP1_STR, PM2_SUP
|
|
Pathogenic
(Aug 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nocturnal frontal lobe epilepsy 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003818685.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Nov 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nocturnal frontal lobe epilepsy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001377586.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 280 of the CHRNA4 protein (p.Ser280Phe). … (more)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 280 of the CHRNA4 protein (p.Ser280Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomaldominant nocturnal frontal lobe epilepsy (ADNFLE) (PMID: 7550350, 22036597). It has also been observed to segregate with disease in related individuals. This variant is also known as S248F. ClinVar contains an entry for this variant (Variation ID: 17498). 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 CHRNA4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CHRNA4 function (PMID: 19020039, 19237585, 22036597). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Sep 09, 2008)
|
no assertion criteria provided
Method: literature only
|
EPILEPSY, NOCTURNAL FRONTAL LOBE, TYPE 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039337.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 13, 2018 |
Comment on evidence:
In affected members of a large Australian kindred with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513) reported by Phillips et al. (1995), Steinlein et … (more)
In affected members of a large Australian kindred with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513) reported by Phillips et al. (1995), Steinlein et al. (1995) used single-strand conformation analysis to identify a C-to-T transition in exon 5 of the CHRNA4 gene, resulting in ser248-to-phe (SER248PHE) substitution in the sixth amino acid position of transmembrane domain 2 (M2) and reduced receptor function. Their numbering was based on the Torpedo californica Chrna4 sequence. Saenz et al. (1999) noted that in the human sequence codon 252 is homologous to the Torpedo codon 248, and they referred to the mutation as ser252 to phe (S252F). Forman et al. (1996) suggested an alternative mechanism for pathogenesis of epilepsy associated with this CHRNA4 mutation. From studies of the mouse muscle alpha-1 nicotinic receptor (100690) noted in Forman et al. (1995), Forman et al. (1996) speculated that the mutation in CHRNA4 may cause receptor hyperactivity that could lead to epileptic activity. In 11 affected members of a large Spanish family with nocturnal frontal lobe epilepsy, Saenz et al. (1999) identified the S252F mutation. Saenz et al. (1999) noted that the clinical features were similar to those reported by Steinlein et al. (1995). This same residue is affected in the S252L mutation (118504.0004) Using PET scans, Fedi et al. (2008) observed decreased striatal D1 receptor (DRD1; 126449) binding, particularly in the right putamen, in 12 individuals with autosomal dominant nocturnal frontal lobe epilepsy and the S252L mutation compared to controls. Decreased D1 receptor binding was postulated to represent receptor downregulation from increased extracellular levels of dopamine. Increased dopamine release may result from a gain-of-function in nAChRs with the mutant CHRNA4 subunit, since nAChRs regulate dopamine release. (less)
|
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 |
---|---|---|---|---|
Mutations in familial nocturnal frontal lobe epilepsy might be associated with distinct neurological phenotypes. | Steinlein OK | Seizure | 2012 | PMID: 22036597 |
Nicotine normalizes intracellular subunit stoichiometry of nicotinic receptors carrying mutations linked to autosomal dominant nocturnal frontal lobe epilepsy. | Son CD | Molecular pharmacology | 2009 | PMID: 19237585 |
Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype. | Zhu G | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2008 | PMID: 19020039 |
Reduced striatal D1 receptor binding in autosomal dominant nocturnal frontal lobe epilepsy. | Fedi M | Neurology | 2008 | PMID: 18685138 |
Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a Ser252Phe mutation in the CHRNA4 gene. | Sáenz A | Archives of neurology | 1999 | PMID: 10448807 |
Exon-intron structure of the human neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4). | Steinlein O | Genomics | 1996 | PMID: 8833159 |
Alternative mechanism for pathogenesis of an inherited epilepsy by a nicotinic AChR mutation. | Forman SA | Nature genetics | 1996 | PMID: 8696332 |
Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q 13.2. | Phillips HA | Nature genetics | 1995 | PMID: 7647781 |
A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. | Steinlein OK | Nature genetics | 1995 | PMID: 7550350 |
A discrete site for general anesthetics on a postsynaptic receptor. | Forman SA | Molecular pharmacology | 1995 | PMID: 7476881 |
Text-mined citations for rs121909580 ...
HelpRecord last updated Mar 17, 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.