NM_000080.4(CHRNE):c.1327del AND Congenital myasthenic syndrome 4C

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 25, 2017
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000020022.40

Allele description [Variation Report for NM_000080.4(CHRNE):c.1327del]

NM_000080.4(CHRNE):c.1327del

Genes:

MINK1:misshapen like kinase 1 [Gene - OMIM - HGNC]
C17orf107:chromosome 17 open reading frame 107 [Gene - HGNC]
CHRNE:cholinergic receptor nicotinic epsilon subunit [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17p13.2

Genomic location:

Preferred name:

NM_000080.4(CHRNE):c.1327del

Other names:

epsilon1267delG; ε1267delG

HGVS:

NC_000017.11:g.4898892del
NG_008029.2:g.9185del
NG_028005.1:g.70553del
NM_000080.4:c.1327delMANE SELECT
NP_000071.1:p.Glu443LysfsTer64
LRG_1254t1:c.1327del
LRG_1254:g.9185del
NC_000017.10:g.4802186del
NC_000017.10:g.4802187del
NM_000080.3:c.1327delG
NM_000080.4:c.1327delGMANE SELECT
p.Glu443Lysfs*64

Links:

OMIM: 100725.0012; dbSNP: rs763258280

NCBI 1000 Genomes Browser:

rs763258280

Molecular consequence:

NM_000080.4:c.1327del - splice acceptor variant - [Sequence Ontology: SO:0001574]

Functional consequence:

Unknown function

Observations:

Condition(s)

Name:: Congenital myasthenic syndrome 4C (CMS4C)
Synonyms:: Myasthenic syndrome, congenital, associated with acetylcholine receptor deficiency; Myasthenic syndrome, congenital, postsynaptic, associated with acetylcholine receptor deficiency
Identifiers:: MONDO: MONDO:0012157; MedGen: C1837091; Orphanet: 590; OMIM: 608931

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000040320	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2004)	germline	literature only	PubMed (6) [See all records that cite these PMIDs] 10534268, 10514102, 10496269, 9097970, 15322984, 15367858
SCV000680173	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Oct 25, 2017)	germline	clinical testing	Citation Link,
SCV000807240	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9668239, 10514102, 25741868, 25326635
SCV004023365	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	biparental	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004101549	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	biparental	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	3	not provided	not provided	3	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

A common mutation (epsilon1267delG) in congenital myasthenic patients of Gypsy ethnic origin.

Abicht A, Stucka R, Karcagi V, Herczegfalvi A, Horváth R, Mortier W, Schara U, Ramaekers V, Jost W, Brunner J, Janssen G, Seidel U, Schlotter B, Müller-Felber W, Pongratz D, Rüdel R, Lochmüller H.

Neurology. 1999 Oct 22;53(7):1564-9.

PubMed [citation]

PMID:: 10534268

Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene.

Middleton L, Ohno K, Christodoulou K, Brengman J, Milone M, Neocleous V, Serdaroğlu P, Deymeer F, Ozdemir C, Mubaidin A, Horany K, Al-Shehab A, Mavromatis I, Mylonas I, Tsingis M, Zamba E, Pantzaris M, Kyriallis K, Engel AG.

Neurology. 1999 Sep 22;53(5):1076-82.

PubMed [citation]

PMID:: 10496269

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000040320.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680173.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	not provided	1	not provided	not provided	clinical testing	not provided
3	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	blood	not provided		1	not provided	not provided	not provided
2	germline	yes	1	blood	not provided		1	not provided	not provided	not provided
3	germline	yes	1	blood	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV000807240.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing (GTR000508680.4)	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided	(GTR000508680.4)	not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV004023365.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	biparental	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004101549.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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