ClinVar Miner

Submissions for variant NM_000080.4(CHRNE):c.865C>T (p.Leu289Phe)

dbSNP: rs121909511
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000020012 SCV000820404 pathogenic Congenital myasthenic syndrome 4A 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 289 of the CHRNE protein (p.Leu289Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant congenital myasthenic syndrome (PMID: 7538206, 8872460, 21822932, 27779167). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18344). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHRNE protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CHRNE function (PMID: 8872460). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago RCV001818167 SCV002069273 likely pathogenic not provided 2018-11-06 criteria provided, single submitter clinical testing DNA sequence analysis of the CHRNE gene demonstrated the likely pathogenic sequence change, c.865C>T in exon 8, that results in an amino acid change, p.Leu289Phe. The p.Leu289Phe change affects a highly conserved amino acid residue located in a domain of the CHRNE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu289Phe substitution. This particular amino acid change (previously reported as p.Leu269Phe) has been described in patients with slow-channel congenital myasthenic syndrome (PMID: 8872460, 7538206, 27779167). Functional expression studies showed that the p.Leu289Phe mutation slowed the rate of acetylcholine receptor channel closure and increased the apparent affinity for acetylcholine. The mutation also caused pathologic channel openings even in the absence of acetylcholine, resulting in a leaky channel (PMID: 8872460).
OMIM RCV000020012 SCV000040310 pathogenic Congenital myasthenic syndrome 4A 1996-09-01 no assertion criteria provided literature only

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