Submissions for variant NM_000080.4(CHRNE):c.1297_1314dup (p.Ser433_Glu438dup)

dbSNP: rs1969834618

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044724	SCV001208537	likely pathogenic	Congenital myasthenic syndrome 4A	2019-12-30	criteria provided, single submitter	clinical testing	This variant, c.1297_1314dup, results in the insertion of 6 amino acid(s) to the CHRNE protein (p.Ser433_Glu438dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 9539130). It has also been observed to segregate with disease in related individuals. This variant is also known as 1254ins18 in the literature. This variant has been reported to affect CHRNE protein function (PMID: 9539130). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV001044724	SCV004212563	likely pathogenic	Congenital myasthenic syndrome 4A	2023-10-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526070	SCV005039973	likely pathogenic	Congenital myasthenic syndrome	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: CHRNE c.1297_1314dup18 (p.Ser433_Glu438dup) results in an in-frame duplication that is predicted to duplicate 6 amino acids into the encoded protein. The variant was absent in 230276 control chromosomes. c.1297_1314dup18 has been reported in the literature in trans along with a second pathogenic missense in at-least three individuals from a family affected with Congenital Myasthenic Syndrome (example, Milone_1998). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significantly reduced neuromuscular endplate metrics, abnormally brief activation episodes during steady state agonist application and electrically silence during the synaptic response to acetylcholine, in patients tissues and in engineered HEK cells. The endplate deficiency can be restored via simplification of the postsynaptic region and fetal AChR rescue (Milone_1998). The following publication have been ascertained in the context of this evaluation (PMID: 9539130). ClinVar contains an entry for this variant (Variation ID: 842325). Based on the evidence outlined above, the variant was classified as likely pathogenic.