ClinVar Genomic variation as it relates to human health
NM_000744.7(CHRNA4):c.851C>T (p.Ser284Leu)
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_000744.7(CHRNA4):c.851C>T (p.Ser284Leu)
Variation ID: 17500 Accession: VCV000017500.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.33 20: 63350560 (GRCh38) [ NCBI UCSC ] 20: 61981912 (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 3, 2013 Feb 14, 2024 Jul 6, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000744.7:c.851C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000735.1:p.Ser284Leu missense NM_001256573.2:c.323C>T NP_001243502.1:p.Ser108Leu missense NR_046317.2:n.1060C>T non-coding transcript variant NC_000020.11:g.63350560G>A NC_000020.10:g.61981912G>A NG_011931.1:g.15784C>T - Protein change
- S284L, S108L
- Other names
- S252L
- p.S284L:TCG>TTG
- Canonical SPDI
- NC_000020.11:63350559: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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CHRNA4 | - | - |
GRCh38 GRCh37 |
870 | 1126 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Feb 2, 2022 | RCV000019052.42 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 11, 2014 | RCV000186931.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 6, 2022 | RCV000692832.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 16, 2016 | RCV002316197.8 |
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
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
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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 11, 2014)
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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: SCV000240502.11
First in ClinVar: Aug 07, 2015 Last updated: Aug 07, 2015 |
Comment:
p.Ser284Leu (TCG>TTG): c.851 C>T in exon 5 of the CHRNA4 gene (NM_000744.5)The S284L missense change was initially found to segregate with autosomal dominant nocturnal frontal … (more)
p.Ser284Leu (TCG>TTG): c.851 C>T in exon 5 of the CHRNA4 gene (NM_000744.5)The S284L missense change was initially found to segregate with autosomal dominant nocturnal frontal lobe epilepsy (NFLE) in four affected individuals in a Japanese family (Hirose et al., 1999). It has subsequently been identified as a de novo mutation in sporadic NFLE and in multiple families with autosomal dominant NFLE, and individuals with S284L are frequently reported to have drug-resistant seizures and/or intellectual disability (Phillips et al., 2001; Rozycka et al., 2003; Cho et al., 2003; Hwang et al., 2011). Functional studies in rats indicate that S284L results in abnormalities in GABAergic transmission (Zhu et al., 2008). S284L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. It occurs at a highly conserved position within the 2nd transmembrane domain, which forms the wall of the ionic pore. Therefore, S284L is a pathogenic mutation. The variant is found in CHILD-EPI panel(s). (less)
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Pathogenic
(Apr 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nocturnal frontal lobe epilepsy 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001571374.1
First in ClinVar: Apr 18, 2021 Last updated: Apr 18, 2021 |
Family history: no
Secondary finding: no
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nocturnal frontal lobe epilepsy 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557236.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (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. 0600 - Variant is located in the annotated neurotransmitter-gated ion-channel transmembrane domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in many individuals with nocturnal frontal lobe epilepsy (ClinVar, PMID: 10563623, PMID: 14623738). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in multi-generation families (PMID: 10563623, PMID: 14623738). (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
(Jul 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nocturnal frontal lobe epilepsy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000820675.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CHRNA4 function (PMID: 19020039, 19237585, 22036597). … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CHRNA4 function (PMID: 19020039, 19237585, 22036597). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 17500). This variant is also known as c.755C>T (p.Ser252Leu). This missense change has been observed in individual(s) with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (PMID: 10563623, 10939581, 12887446, 14623738, 22118295). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 284 of the CHRNA4 protein (p.Ser284Leu). (less)
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Pathogenic
(Sep 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000851804.3
First in ClinVar: Nov 08, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.S284L pathogenic mutation (also known as c.851C>T), located in coding exon 5 of the CHRNA4 gene, results from a C to T substitution at … (more)
The p.S284L pathogenic mutation (also known as c.851C>T), located in coding exon 5 of the CHRNA4 gene, results from a C to T substitution at nucleotide position 851. The serine at codon 284 is replaced by leucine, an amino acid with dissimilar properties. This pathogenic mutation segregated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in multiple families in the literature; some of these individuals had varying levels of intellectual disability and some were not responsive to seizure medication (Hirose S et al. Neurology, 1999 Nov;53:1749-53; Rozycka A et al. Epilepsia, 2003 Aug;44:1113-7; Cho YW et al. Arch. Neurol., 2003 Nov;60:1625-32). Functional studies found that this mutation results in faster desensitization when expressed in Xenopus oocytes, which is consistent with a loss of function mutation (Matsushima N et al. Epilepsy Res., 2002 Feb;48:181-6). In addition, rats with this mutation showed attenuation of synaptic and extrasynaptic GABAergic transmission with an NFLE phenotype (Zhu G et al. J. Neurosci., 2008 Nov;28:12465-76). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 01, 2011)
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no assertion criteria provided
Method: literature only
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EPILEPSY, NOCTURNAL FRONTAL LOBE, TYPE 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039339.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
In a Japanese family with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513), Hirose et al. (1999) identified a 755C-T transition in exon 5 of … (more)
In a Japanese family with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513), Hirose et al. (1999) identified a 755C-T transition in exon 5 of the CHRNA4 gene, causing a ser252-to-leu (S252L) substitution. The mutation was not found in 200 alleles of healthy volunteers. Based on analysis of the amino acid sequence, Hirose et al. (1999) suggested that the serine-to-leucine change undermines the channel function considerably. In a Korean family in which 9 members in 3 generations were affected with ENFL1, Cho et al. (2003) identified the S252L mutation. Cho et al. (2003) noted that the clinical phenotype in the Korean family was similar to that reported by Hirose et al. (1999) in the Japanese family with the same mutation. Shared features included mental retardation and drug resistance. This same residue is affected in the S252F mutation (118504.0002). By haplotype analysis, Hwang et al. (2011) determined that the common mutation identified by Hirose et al. (1999) and Cho et al. (2003), which Hwang et al. (2011) referred to as ser284-to-leu (S284L), did not arise from a common founder, but rather occurred independently. The mutation was associated with a CpG hypermutable site. (less)
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Likely pathogenic
(Nov 16, 2016)
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no assertion criteria provided
Method: clinical testing
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Epilepsy, nocturnal frontal lobe, type 1
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000804969.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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not provided
(-)
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no classification provided
Method: literature only
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Autosomal dominant nocturnal frontal lobe epilepsy 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000057845.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy. | Adam MP | - | 2023 | PMID: 20301348 |
Functional characterization of a CRH missense mutation identified in an ADNFLE family. | Sansoni V | PloS one | 2013 | PMID: 23593457 |
Autism in siblings with autosomal dominant nocturnal frontal lobe epilepsy. | Miyajima T | Brain & development | 2013 | PMID: 22883468 |
A de novo mutation in an Italian sporadic patient affected by nocturnal frontal lobe epilepsy. | Sansoni V | Journal of sleep research | 2012 | PMID: 22118295 |
Mutations in familial nocturnal frontal lobe epilepsy might be associated with distinct neurological phenotypes. | Steinlein OK | Seizure | 2012 | PMID: 22036597 |
Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 Ser284Leu mutation. | Hwang SK | Journal of human genetics | 2011 | PMID: 21753767 |
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 |
A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation. | Cho YW | Archives of neurology | 2003 | PMID: 14623738 |
Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor alpha 4 subunit associated with frontal lobe epilepsy causes faster desensitization of the rat receptor expressed in oocytes. | Matsushima N | Epilepsy research | 2002 | PMID: 11904236 |
A de novo mutation in sporadic nocturnal frontal lobe epilepsy. | Phillips HA | Annals of neurology | 2000 | PMID: 10939581 |
Electroclinical picture of autosomal dominant nocturnal frontal lobe epilepsy in a Japanese family. | Ito M | Epilepsia | 2000 | PMID: 10643924 |
A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. | Hirose S | Neurology | 1999 | PMID: 10563623 |
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Text-mined citations for rs28931591 ...
HelpRecord last updated Apr 20, 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.