Submissions for variant NM_000080.4(CHRNE):c.183_187dup (p.Leu63fs)

gnomAD frequency: 0.00002  dbSNP: rs776927709

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493520	SCV000581834	pathogenic	not provided	2017-05-04	criteria provided, single submitter	clinical testing	The c.183_187dupCTCAC pathogenic variant in the CHRNE gene has been reported previously using alternative nomenclature (c.123_127dupCTCAC), in both compound heterozygous and homozygous states, in individuals with congenital myasthenia (Ohno et al., 1997; Salih et al., 2011). The c.183_187dupCTCAC variant causes a frameshift starting with codon Leucine 63, changes this amino acid to a Proline residue and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Leu63ProfsX3. This variant is expected to cause loss of normal protein function either through nonsense-mediated mRNA decay or protein truncation. Functional studies indicate that CHRNE protein harboring the c.183_187dupCTCAC variant fails to assemble with the alpha subunit of the AChR (Ohno et al., 1997). The c.183_187dupCTCAC variant is not observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server). We interpret c.183_187dupCTCAC as a pathogenic variant.
Illumina Laboratory Services, Illumina	RCV000779224	SCV000915769	likely pathogenic	Congenital myasthenic syndrome	2017-07-10	criteria provided, single submitter	clinical testing	The CHRNE c.183_187dupCTCAC (p.Leu63ProfsTer3) variant is a frameshift variant that is predicted to cause premature truncation of the protein. Across three studies of patients with congenital myasthenic syndrome, the p.Leu63ProfsTer3 variant has been identified in a homozygous state in four patients including three siblings from a consanguineous family, and in a compound heterozygous state in two affected siblings (Ohno et al. 1997; Salih et al. 2011; Chang et al. 2016). The p.Leu63ProfsTer3 variant was absent from 100 controls and is reported at a frequency of 0.00051 in the Ashkenazi Jewish population of the Genome Aggregation Database. Ohno et al. (1997) demonstrated in cultured cells that the p.Leu63ProfsTer3 variant leads to significantly reduced expression of the epsilon subunit of the acetylcholine receptor (CHRNE) compared to wild type. Based on the evidence, the p.Leu63ProfsTer3 variant is classified as likely pathogenic for the recessive form of congenital myasthenic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001384427	SCV001583923	pathogenic	Congenital myasthenic syndrome 4A	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu63Profs*3) in the CHRNE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHRNE are known to be pathogenic (PMID: 22678886). This variant is present in population databases (rs776927709, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with autosomal recessive congenital myasthenic syndrome (PMID: 9158150, 21150643, 27717316). It has also been observed to segregate with disease in related individuals. This variant is also known as 127ins5 and 123_127dupCTCAC. ClinVar contains an entry for this variant (Variation ID: 429303). For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814166	SCV001755366	pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001384427	SCV004217771	pathogenic	Congenital myasthenic syndrome 4A	2023-10-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000779224	SCV001453139	pathogenic	Congenital myasthenic syndrome	2020-09-16	no assertion criteria provided	clinical testing