ClinVar Miner

Submissions for variant NM_000080.4(CHRNE):c.1353dup (p.Asn452fs)

dbSNP: rs773526895
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479377 SCV000566469 pathogenic not provided 2022-11-07 criteria provided, single submitter clinical testing 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)
Labcorp Genetics (formerly Invitae), Labcorp RCV000804085 SCV000943979 pathogenic Congenital myasthenic syndrome 4A 2024-01-24 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV000020024 SCV001163793 pathogenic Congenital myasthenic syndrome 4C criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000479377 SCV002019311 pathogenic not provided 2022-04-30 criteria provided, single submitter clinical testing
New York Genome Center RCV001836761 SCV002097793 pathogenic Congenital myasthenic syndrome 4A; Congenital myasthenic syndrome 4C; Congenital myasthenic syndrome 4B 2021-03-19 criteria provided, single submitter clinical testing
3billion RCV002250605 SCV002521083 pathogenic Congenital myasthenic syndrome 4B 2022-05-22 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%). 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.
Fulgent Genetics, Fulgent Genetics RCV001836761 SCV002811473 pathogenic Congenital myasthenic syndrome 4A; Congenital myasthenic syndrome 4C; Congenital myasthenic syndrome 4B 2022-02-16 criteria provided, single submitter clinical testing
Baylor Genetics RCV000804085 SCV004212566 pathogenic Congenital myasthenic syndrome 4A 2024-03-27 criteria provided, single submitter clinical testing
OMIM RCV000020024 SCV000040322 pathogenic Congenital myasthenic syndrome 4C 2008-12-09 no assertion criteria provided literature only
GeneReviews RCV000235035 SCV000292399 not provided Congenital myasthenic syndrome no assertion provided literature only
Natera, Inc. RCV000235035 SCV001453121 pathogenic Congenital myasthenic syndrome 2020-09-16 no assertion criteria provided clinical testing

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