ClinVar Genomic variation as it relates to human health
NM_000080.4(CHRNE):c.1353dup (p.Asn452fs)
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_000080.4(CHRNE):c.1353dup (p.Asn452fs)
Variation ID: 243032 Accession: VCV000243032.21
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 17p13.2 17: 4898864-4898865 (GRCh38) [ NCBI UCSC ] 17: 4802159-4802160 (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 Jul 25, 2016 Feb 28, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000080.4:c.1353dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000071.1:p.Asn452fs frameshift NM_000080.4:c.1353dupG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
frameshift NM_000080.3:c.1353dup NC_000017.11:g.4898868dup NC_000017.10:g.4802163dup NG_008029.2:g.9211dup NG_028005.1:g.70529dup LRG_1254:g.9211dup LRG_1254t1:c.1353dup LRG_1254p1:p.Asn452fs - Protein change
- N452fs
- Other names
- epsilon1293insG
- e1293insG
- Canonical SPDI
- NC_000017.11:4898864:CCCC:CCCCC
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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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CHRNE | - | - |
GRCh38 GRCh37 |
340 | 1314 |
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 (2) |
criteria provided, single submitter
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- | RCV000020024.29 | |
Pathogenic (2) |
no assertion criteria provided
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Sep 16, 2020 | RCV000235035.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 7, 2022 | RCV000479377.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000804085.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2022 | RCV001836761.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 22, 2022 | RCV002250605.1 |
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
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital myasthenic syndrome 4C
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163793.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Mar 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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Congenital myasthenic syndrome 4A
Congenital myasthenic syndrome 4B Congenital myasthenic syndrome 4C
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002097793.1 First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022 |
Clinical Features:
Autism (present) , Macrocephaly (present) , Global developmental delay (present) , Attention deficit hyperactivity disorder (present) , Cafe-au-lait spot (present)
Secondary finding: no
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital myasthenic syndrome 4B
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521083.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.013%). Frameshift: predicted to result in a loss … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.013%). Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 8957026). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000243032 / PMID: 8957026). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Weakness of facial musculature (present) , Ptosis (present) , Abnormal synaptic transmission at the neuromuscular junction (present) , Ophthalmoplegia (present)
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Pathogenic
(Feb 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital myasthenic syndrome 4A
Congenital myasthenic syndrome 4C Congenital myasthenic syndrome 4B
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811473.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 07, 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: SCV000566469.7
First in ClinVar: Apr 27, 2017 Last updated: May 06, 2023 |
Comment:
Reported previously using alternate nomenclature (c.1293insG) in multiple individuals with congenital myasthenia, and is noted to be a founder mutation in Northern Africa (Beeson et … (more)
Reported previously using alternate nomenclature (c.1293insG) in multiple individuals with congenital myasthenia, and is noted to be a founder mutation in Northern Africa (Beeson et al., 2005; Richard et al., 2008; Mihaylova et al., 2010; Maselli et al., 2011); Published functional studies demostrate severely reduced cell surface expression and absent channel activity (Engel et al., 1996); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 42 amino acids are lost and replaced with three incorrect amino acids; This variant is associated with the following publications: (PMID: 20301347, 15951177, 8957026, 19064877, 20562457, 21175599, 29054425, 31589614, 10976646, 12536367) (less)
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Pathogenic
(Oct 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital myasthenic syndrome 4A
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004212566.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Apr 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019311.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital myasthenic syndrome 4A
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000943979.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asn452Glufs*4) in the CHRNE gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Asn452Glufs*4) in the CHRNE gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the CHRNE protein. This variant is present in population databases (rs773526895, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with autosomal recessive congenital myasthenic syndrome (PMID: 8957026, 15951177, 19064877, 21175599, 28024842, 29054425). This variant is also known as 1293insG. ClinVar contains an entry for this variant (Variation ID: 243032). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CHRNE function (PMID: 8957026). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 09, 2008)
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no assertion criteria provided
Method: literature only
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MYASTHENIC SYNDROME, CONGENITAL, 4C, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000040322.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
Richard et al. (2008) identified a homozygous 1-bp insertion (c.1293insG) in the CHRNE gene in 14 (60%) of 23 North African families with congenital myasthenic … (more)
Richard et al. (2008) identified a homozygous 1-bp insertion (c.1293insG) in the CHRNE gene in 14 (60%) of 23 North African families with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931). All 14 families were consanguineous; 9 originated from Algeria, 3 from Tunisia, and 1 each from Morocco and Libya. Haplotype analysis indicated a founder effect that occurred about 700 years ago. The phenotype was relatively homogeneous without fetal involvement and with moderate hypotonia and oculobulbar involvement, mild and stable disease course, and good response to cholinesterase inhibitors. For discussion of the 1293insG mutation in the CHRNE gene that was found in compound heterozygous state in a patient with CMS4C by Engel et al. (1996), see 100725.0013. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Congenital myasthenic syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001453121.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Congenital myasthenic syndrome
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000292399.2
First in ClinVar: Jul 25, 2016 Last updated: Oct 01, 2022
Comment:
Variant of a regulatory element (N-box) in the AChRe promoter region resulting in reduced gene expression.
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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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Congenital Myasthenic Syndromes Overview. | Adam MP | - | 2021 | PMID: 20301347 |
Molecular characterization of congenital myasthenic syndromes in Spain. | Natera-de Benito D | Neuromuscular disorders : NMD | 2017 | PMID: 29054425 |
Congenital myasthenic syndrome in Israel: Genetic and clinical characterization. | Aharoni S | Neuromuscular disorders : NMD | 2017 | PMID: 28024842 |
Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE. | Maselli RA | Clinical genetics | 2011 | PMID: 21175599 |
The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa. | Richard P | Neurology | 2008 | PMID: 19064877 |
126th International Workshop: congenital myasthenic syndromes, 24-26 September 2004, Naarden, the Netherlands. | Beeson D | Neuromuscular disorders : NMD | 2005 | PMID: 15951177 |
End-plate acetylcholine receptor deficiency due to nonsense mutations in the epsilon subunit. | Engel AG | Annals of neurology | 1996 | PMID: 8957026 |
Text-mined citations for rs773526895 ...
HelpRecord last updated May 08, 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.