Submissions for variant NM_000080.4(CHRNE):c.1327del

dbSNP: rs763258280

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516854	SCV000612746	pathogenic	not provided	2016-12-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556621	SCV000641247	pathogenic	Congenital myasthenic syndrome 4A	2023-11-25	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000020022	SCV000680173	pathogenic	Congenital myasthenic syndrome 4C	2017-10-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000516854	SCV000709960	pathogenic	not provided	2024-07-29	criteria provided, single submitter	clinical testing	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)
Baylor Genetics	RCV000020022	SCV000807240	pathogenic	Congenital myasthenic syndrome 4C	2017-09-01	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000516854	SCV001249976	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001169937	SCV001251718	pathogenic	Congenital myasthenic syndrome 4B	2020-05-03	criteria provided, single submitter	clinical testing
Suma Genomics	RCV001835737	SCV002097026	pathogenic	Congenital myasthenic syndrome 4A; Congenital myasthenic syndrome 4C; Congenital myasthenic syndrome 4B		criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000556621	SCV002569381	pathogenic	Congenital myasthenic syndrome 4A	2022-02-07	criteria provided, single submitter	clinical testing	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.
3billion	RCV001169937	SCV003841633	pathogenic	Congenital myasthenic syndrome 4B	2023-02-23	criteria provided, single submitter	clinical testing	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.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000020022	SCV004023365	pathogenic	Congenital myasthenic syndrome 4C		criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338479	SCV004047730	pathogenic	Congenital myasthenic syndrome 1A		criteria provided, single submitter	clinical testing	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
Neuberg Centre For Genomic Medicine, NCGM	RCV000556621	SCV004048044	pathogenic	Congenital myasthenic syndrome 4A		criteria provided, single submitter	clinical testing	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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000020022	SCV004101549	pathogenic	Congenital myasthenic syndrome 4C		criteria provided, single submitter	clinical testing	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000556621	SCV004171251	pathogenic	Congenital myasthenic syndrome 4A	2023-11-30	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001169937	SCV004176607	pathogenic	Congenital myasthenic syndrome 4B	2023-03-01	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000556621	SCV004212564	pathogenic	Congenital myasthenic syndrome 4A	2024-03-24	criteria provided, single submitter	clinical testing
OMIM	RCV000020022	SCV000040320	pathogenic	Congenital myasthenic syndrome 4C	2004-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000235026	SCV000292398	not provided	Congenital myasthenic syndrome		no assertion provided	literature only
Natera, Inc.	RCV000235026	SCV001453122	pathogenic	Congenital myasthenic syndrome	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000516854	SCV002035189	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000516854	SCV002038349	pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000556621	SCV004099478	pathogenic	Congenital myasthenic syndrome 4A	2023-10-30	no assertion criteria provided	clinical testing