rs121909511

chr17-4900845-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000080.4(CHRNE):c.865C>T(p.Leu289Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L289V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.80

Genes affected

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

C17orf107 (HGNC:37238): (chromosome 17 open reading frame 107)

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000080.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 17-4900845-G-A is Pathogenic according to our data. Variant chr17-4900845-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4900845-G-A is described in Lovd as [Pathogenic]. Variant chr17-4900845-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNE	NM_000080.4	c.865C>T	p.Leu289Phe	missense_variant	8/12	ENST00000649488.2
C17orf107	NM_001145536.2	c.*312G>A		3_prime_UTR_variant	3/3	ENST00000381365.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNE	ENST00000649488.2	c.865C>T	p.Leu289Phe	missense_variant	8/12		NM_000080.4	P1
C17orf107	ENST00000381365.4	c.*312G>A		3_prime_UTR_variant	3/3	2	NM_001145536.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 4A Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 06, 2018

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.88		Gain of methylation at K293 (P = 0.0666);Gain of methylation at K293 (P = 0.0666);
MVP		0.94
MPC		0.73
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909511; hg19: chr17-4804140;