VCV000243031.60 - ClinVar

NM_000080.4(CHRNE):c.1327del

Germline

Classification

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.

(23)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000080.4(CHRNE):c.1327del

Variation ID: 243031 Accession: VCV000243031.60

Type and length

Deletion, 1 bp

Location

Cytogenetic: 17p13.2 17: 4898891 (GRCh38) [ NCBI UCSC ] 17: 4802186 (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	Jul 20, 2016	Oct 20, 2024	Jul 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000080.4:c.1327del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_000080.4:c.1327delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NC_000017.11:g.4898892del
NC_000017.10:g.4802187del
NG_008029.2:g.9185del
NG_028005.1:g.70553del
LRG_1254:g.9185del
LRG_1254t1:c.1327del
	NP_000071.1:p.Glu443LysfsTer64

... more HGVS ... less HGVS

Protein change

Other names

epsilon1267delG
e1267delG

Canonical SPDI

NC_000017.11:4898890:CC:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Unknown function

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA8313854 Leiden Muscular Dystrophy (CHRNE): CHRNE_00018 OMIM: 100725.0012 dbSNP: rs763258280 VarSome

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
Gene	OMIM	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.
C17orf107	-	-	-	GRCh38 GRCh37	-	780
CHRNE		-	-	GRCh38 GRCh37	346	1336
MINK1		-	-	GRCh38 GRCh37	74	130

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.
Congenital myasthenic syndrome 4C	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 25, 2017	RCV000020022.40
Congenital myasthenic syndrome	Pathogenic (2)	no assertion criteria provided	Sep 16, 2020	RCV000235026.6
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jul 29, 2024	RCV000516854.33
Congenital myasthenic syndrome 4A	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 24, 2024	RCV000556621.20
Congenital myasthenic syndrome 4B	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 1, 2023	RCV001169937.7
Congenital myasthenic syndrome 4A Congenital myasthenic syndrome 4B Congenital myasthenic syndrome 4C	Pathogenic (1)	criteria provided, single submitter	-	RCV001835737.4
Congenital myasthenic syndrome 1A	Pathogenic (1)	criteria provided, single submitter	-	RCV003338479.3

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 (Dec 30, 2016)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000612746.2 First in ClinVar: Dec 19, 2017 Last updated: Apr 02, 2018	Publications: PubMed (5) PubMed: 10534268‚ 15322984‚ 10514102‚ 9668239‚ 27634344
Pathogenic (Oct 25, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Congenital myasthenic syndrome 4C (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680173.2 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Observation 1: Sex: female Tissue: blood Observation 2: Sex: female Tissue: blood Observation 3: Sex: female Tissue: blood
Pathogenic (Nov 25, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Congenital myasthenic syndrome 4A Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000641247.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 9668239‚ 10496269‚ 10514102‚ 10534268‚ 27634344‚ 15322984‚ 15367858 Comment: This sequence change results in a frameshift in the CHRNE gene (p.Glu443Lysfs64). While this is not anticipated to result in nonsense mediated decay, it is … (more) This sequence change results in a frameshift in the CHRNE gene (p.Glu443Lysfs64). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the CHRNE protein and extend the protein by 12 additional amino acid residues. This variant is present in population databases (rs763258280, gnomAD 0.09%). This frameshift has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 9668239, 10496269, 10514102, 10534268, 27634344). It is commonly reported in individuals of Roma ancestry (PMID: 15322984, 15367858). This variant is also known as c.1267delG. ClinVar contains an entry for this variant (Variation ID: 243031). 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 frameshift affects CHRNE function (PMID: 10514102). 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)
Pathogenic (Jul 29, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000709960.6 First in ClinVar: Apr 02, 2018 Last updated: Sep 16, 2024	Comment: The c.1327delG variant is a common pathogenic variant in individuals of Roma background (PMID: 10534268); Frameshift variant in the C-terminus predicted to result in abnormal … (more) The c.1327delG variant is a common pathogenic variant in individuals of Roma background (PMID: 10534268); Frameshift variant in the C-terminus predicted to result in abnormal protein length, as the last 51 amino acids are lost and replaced with 63 incorrect amino acids; This variant is associated with the following publications: (PMID: 10514102, 10496269, 15367858, 36964972, 15322984, 9668239, 27634344, 28464723, 29056292, 29054425, 30369941, 31589614, 33193787, 34426522, 34008892, 32070632, 31407473, 35175423, 31069529, 10534268) (less)
Pathogenic (May 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4B Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV001251718.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4A Congenital myasthenic syndrome 4B Congenital myasthenic syndrome 4C (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Suma Genomics Accession: SCV002097026.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
Pathogenic (Feb 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002569381.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: A homozygous single base pair deletion c.1267delG in exon 12 of the CHRNE gene that results in a frameshift and premature truncation of the protein … (more) A homozygous single base pair deletion c.1267delG in exon 12 of the CHRNE gene that results in a frameshift and premature truncation of the protein 64 amino acids downstream to codon 443 (p.Glu443LysfsTer64) was detected. The observed variation (c.1267delG) has previously been reported in patients affected with congenital myasthenic syndrome and the variant has been classified as pathogenic by ClinVar database. This variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.15% in the gnomAD . The reference region is conserved across species. (less) Clinical Features: Ptosis (present) , Dysarthria (present) Age: 30-39 years Sex: female Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4C (Autosomal unknown) Affected status: yes Allele origin: germline	Baylor Genetics Accession: SCV000807240.2 First in ClinVar: Feb 08, 2018 Last updated: Dec 11, 2022	Publications: PubMed (3) PubMed: 25326635‚ 9668239‚ 10514102 Comment: This mutation has been previously reported as disease-causing and was found twice in our laboratory in a homozygous state in individuals with myasthenia. One was … (more) This mutation has been previously reported as disease-causing and was found twice in our laboratory in a homozygous state in individuals with myasthenia. One was as 8-year-old male with congenital myasthenia, with a similarly affected sister (not tested); other was a 15-year-old female with myasthenia gravis, mild intellectual disability. (less)
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4B Affected status: yes Allele origin: unknown	3billion Accession: SCV003841633.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 9668239 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.013%). This variant was predicted to result in … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.013%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Multiple pathogenic variants are reported downstream of the variant. This homozygous variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000243031 / PMID: 9668239). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Weakness of facial musculature (present) , Ophthalmoplegia (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4C Affected status: yes Allele origin: biparental	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV004023365.1 First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023	Publications: DOI: 10.1111/ene.14033 DOI: 10.1111/ene.14033
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 1A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004047730.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The frameshift variant c.1327del (p.Glu443LysfsTer64) in CHRNE gene has been reported to segregate with autosomal recessive congenital myasthenic syndrome (CMS) in many families (Natera-de Benito … (more) The frameshift variant c.1327del (p.Glu443LysfsTer64) in CHRNE gene has been reported to segregate with autosomal recessive congenital myasthenic syndrome (CMS) in many families (Natera-de Benito D et.al.,2016). It is a common cause of autosomal recessive CMS in several populations, and has been reported to be a founder mutation in the Roma population (Hantaï D et.al.,2004).This variant has been reported to the ClinVar database as Pathogenic. The p.Glu443LysfsTer64 variant is reported with the allele frequency 0.01276% in gnomAD exomes and novel in 1000 Genomes. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic (less) Clinical Features: Abnormal synaptic transmission at the neuromuscular junction (present) , Muscle weakness (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004048044.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The frameshift variant c.1327del(p.Glu443LysfsTer64) in CHRNE gene has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (Natera-de Benito D et.al.,2016). Experimental studies have … (more) The frameshift variant c.1327del(p.Glu443LysfsTer64) in CHRNE gene has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (Natera-de Benito D et.al.,2016). Experimental studies have shown that this frameshift affects CHRNE function (Yang Y et.al.,2014). This variant has been reported to the ClinVar database as Pathogenic. The p.Glu443LysfsTer64 variant is reported with allele frequency of 0.01% in gnomAD exomes and novel in 1000 Genomes. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Fatigable weakness (present) , Ptosis (present) , Fatigable weakness (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4C (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004101549.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023	Comment: The frame shift c.1327del (p.Glu443LysfsTer64) variant in CHRNE gene has been reported previously in homozygous state associated with congenital myasthenia syndrome. This variant has been … (more) The frame shift c.1327del (p.Glu443LysfsTer64) variant in CHRNE gene has been reported previously in homozygous state associated with congenital myasthenia syndrome. This variant has been reported to segregate with autosomal recessive congenital myasthenic syndrome (CMS) in many families. This variant is predicted to cause loss of normal protein function, as the last 51 amino acids are lost and replaced with 63 incorrect amino acids (Croxen, R et al, Natera-de Benito, D et al.). This variant is reported with the allele frequency 0.01% in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormal synaptic transmission at the neuromuscular junction (present) , Muscle weakness (present)
Pathogenic (Nov 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV004171251.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023	Clinical Features: Hypomimic face (present) , Myopathy (present) , Muscular dystrophy (present) , Proximal muscle weakness (present)
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4B (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004176607.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: The frame shift c.1327del (p.Glu443LysfsTer64) variant has been reported in homozygous and compound heterozygous state in individuals affected with affected with Congenital Myasthenic Syndrome (Parvizi … (more) The frame shift c.1327del (p.Glu443LysfsTer64) variant has been reported in homozygous and compound heterozygous state in individuals affected with affected with Congenital Myasthenic Syndrome (Parvizi Omran S et al. 2019; Durmus H et al. 2018). Experimental studies have shown that this frameshift affects CHRNE function (Croxen R et al. 1999). The p.Glu443LysfsTer64 variant has allele frequency 0.01% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submiters). This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004212564.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Oct 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249976.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 8
Pathogenic (Oct 01, 2004)	no assertion criteria provided Method: literature only	MYASTHENIC SYNDROME, CONGENITAL, 4C, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000040320.3 First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016	Publications: PubMed (6) PubMed: 10534268‚ 10514102‚ 10496269‚ 9097970‚ 15322984‚ 15367858 Comment on evidence: In 13 patients from 11 Gypsy families with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931), Abicht et al. (1999) identified a homozygous 1-bp … (more) In 13 patients from 11 Gypsy families with congenital myasthenic syndrome-4C associated with AChR deficiency (CMS4C; 608931), Abicht et al. (1999) identified a homozygous 1-bp deletion in exon 12 of the CHRNE gene (c.1267delG). All families were of Gypsy or southeastern European origin. Genotype analysis indicated that they derived from a common ancestor. In patients from India and Pakistan with CMS and AChR deficiency, Croxen et al. (1999) identified the 1267delG mutation in exon 12 of the CHRNE gene. Middleton et al. (1999) identified a homozygous c.1267delG mutation in affected members of 5 families with CMS4C previously reported by Christodoulou et al. (1997). Four of the families were of Gypsy descent. Morar et al. (2004) used the 1267delG mutation and 4 other private mutations among the Roma (Gypsies) to infer some of the missing parameters relevant to the comprehensive characterization of the population history of the Gypsies. Sharing of mutations and high carrier rates supported a strong founder effect. The identity of the congenital myasthenia 1267delG mutation in Gypsy and Indian/Pakistani chromosomes provided strong evidence for the Indian origins of the Gypsies. Hantai et al. (2004) reported a carrier rate of 3.74% for the 1267delG mutation in these ethnic groups. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Congenital myasthenic syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453122.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002035189.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002038349.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021
Pathogenic (Oct 30, 2023)	no assertion criteria provided Method: clinical testing	Congenital myasthenic syndrome 4A Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004099478.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023
not provided (-)	no classification provided Method: literature only	Congenital myasthenic syndrome Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000292398.2 First in ClinVar: Jul 20, 2016 Last updated: Oct 01, 2022 Comment: Variant of a regulatory element (N-box) in the AChRε promoter region resulting in reduced gene expression.	Publications: PubMed (2) PubMed: 10534268‚ 15322984 BookShelf: NBK1168 BookShelf: NBK1168
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Comment:

This sequence change results in a frameshift in the CHRNE gene (p.Glu443Lysfs*64). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the CHRNE protein and extend the protein by 12 additional amino acid residues. This variant is present in population databases (rs763258280, gnomAD 0.09%). This frameshift has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 9668239, 10496269, 10514102, 10534268, 27634344). It is commonly reported in individuals of Roma ancestry (PMID: 15322984, 15367858). This variant is also known as c.1267delG. ClinVar contains an entry for this variant (Variation ID: 243031). 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 frameshift affects CHRNE function (PMID: 10514102). 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.

Comment:

The c.1327delG variant is a common pathogenic variant in individuals of Roma background (PMID: 10534268); Frameshift variant in the C-terminus predicted to result in abnormal protein length, as the last 51 amino acids are lost and replaced with 63 incorrect amino acids; This variant is associated with the following publications: (PMID: 10514102, 10496269, 15367858, 36964972, 15322984, 9668239, 27634344, 28464723, 29056292, 29054425, 30369941, 31589614, 33193787, 34426522, 34008892, 32070632, 31407473, 35175423, 31069529, 10534268)

Comment:

A homozygous single base pair deletion c.1267delG in exon 12 of the CHRNE gene that results in a frameshift and premature truncation of the protein 64 amino acids downstream to codon 443 (p.Glu443LysfsTer64) was detected. The observed variation (c.1267delG) has previously been reported in patients affected with congenital myasthenic syndrome and the variant has been classified as pathogenic by ClinVar database. This variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.15% in the gnomAD . The reference region is conserved across species.

Comment:

This mutation has been previously reported as disease-causing and was found twice in our laboratory in a homozygous state in individuals with myasthenia. One was as 8-year-old male with congenital myasthenia, with a similarly affected sister (not tested); other was a 15-year-old female with myasthenia gravis, mild intellectual disability.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.013%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Multiple pathogenic variants are reported downstream of the variant. This homozygous variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000243031 / PMID: 9668239). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The frameshift variant c.1327del (p.Glu443LysfsTer64) in CHRNE gene has been reported to segregate with autosomal recessive congenital myasthenic syndrome (CMS) in many families (Natera-de Benito D et.al.,2016). It is a common cause of autosomal recessive CMS in several populations, and has been reported to be a founder mutation in the Roma population (Hantaï D et.al.,2004).This variant has been reported to the ClinVar database as Pathogenic. The p.Glu443LysfsTer64 variant is reported with the allele frequency 0.01276% in gnomAD exomes and novel in 1000 Genomes. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic

Comment:

The frameshift variant c.1327del(p.Glu443LysfsTer64) in CHRNE gene has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (Natera-de Benito D et.al.,2016). Experimental studies have shown that this frameshift affects CHRNE function (Yang Y et.al.,2014). This variant has been reported to the ClinVar database as Pathogenic. The p.Glu443LysfsTer64 variant is reported with allele frequency of 0.01% in gnomAD exomes and novel in 1000 Genomes. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

The frame shift c.1327del (p.Glu443LysfsTer64) variant in CHRNE gene has been reported previously in homozygous state associated with congenital myasthenia syndrome. This variant has been reported to segregate with autosomal recessive congenital myasthenic syndrome (CMS) in many families. This variant is predicted to cause loss of normal protein function, as the last 51 amino acids are lost and replaced with 63 incorrect amino acids (Croxen, R et al, Natera-de Benito, D et al.). This variant is reported with the allele frequency 0.01% in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

The frame shift c.1327del (p.Glu443LysfsTer64) variant has been reported in homozygous and compound heterozygous state in individuals affected with affected with Congenital Myasthenic Syndrome (Parvizi Omran S et al. 2019; Durmus H et al. 2018). Experimental studies have shown that this frameshift affects CHRNE function (Croxen R et al. 1999). The p.Glu443LysfsTer64 variant has allele frequency 0.01% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submiters). This variant causes a frameshift starting with codon Glutamic Acid 443, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 64 of the new reading frame, denoted p.Glu443LysfsTer64. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Unknown function			Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002569381.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Congenital Myasthenic Syndromes Overview.	Adam MP	-	2021	PMID: 20301347
Genotype-guided diagnostic reassessment after exome sequencing in neuromuscular disorders: experiences with a two-step approach.	Krenn M	European journal of neurology	2020	DOI: 10.1111/ene.14033
Phenotypic heterogeneity in two large Roma families with a congenital myasthenic syndrome due to CHRNE 1267delG mutation. A long-term follow-up.	Natera-de Benito D	Neuromuscular disorders : NMD	2016	PMID: 27634344
Congenital myasthenic syndromes.	Hantaï D	Current opinion in neurology	2004	PMID: 15367858
Mutation history of the roma/gypsies.	Morar B	American journal of human genetics	2004	PMID: 15322984
A common mutation (epsilon1267delG) in congenital myasthenic patients of Gypsy ethnic origin.	Abicht A	Neurology	1999	PMID: 10534268
Novel functional epsilon-subunit polypeptide generated by a single nucleotide deletion in acetylcholine receptor deficiency congenital myasthenic syndrome.	Croxen R	Annals of neurology	1999	PMID: 10514102
Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene.	Middleton L	Neurology	1999	PMID: 10496269
A single nucleotide deletion in the epsilon subunit of the acetylcholine receptor (AChR) in five congenital myasthenic syndrome patients with AChR deficiency.	Croxen R	Annals of the New York Academy of Sciences	1998	PMID: 9668239
Mapping of the familial infantile myasthenia (congenital myasthenic syndrome type Ia) gene to chromosome 17p with evidence of genetic homogeneity.	Christodoulou K	Human molecular genetics	1997	PMID: 9097970

Text-mined citations for rs763258280 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000080.4(CHRNE):c.1327del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs763258280 ...