rs121909515

Positions:

• chr17-4899509-G-A
• chr17-4899509-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000080.4(CHRNE):​c.991C>T​(p.Arg331Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000965 in 1,451,402 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R331Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.14

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 topological_domain Cytoplasmic (size 127) in uniprot entity ACHE_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000080.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-4899508-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 17-4899509-G-A is Pathogenic according to our data. Variant chr17-4899509-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4899509-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.991C>T	p.Arg331Trp	missense_variant	9/12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2			upstream_gene_variant		ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.991C>T	p.Arg331Trp	missense_variant	9/12		NM_000080.4	ENSP00000497829	P1
C17orf107	ENST00000381365.4			upstream_gene_variant		2	NM_001145536.2	ENSP00000370770	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000432 AC: 1 AN: 231394 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000961

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000965 AC: 14 AN: 1451402 Hom.: 0 Cov.: 34 AF XY: 0.00000971 AC XY: 7 AN XY: 720770

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000279 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 4A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 331 of the CHRNE protein (p.Arg331Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 9158150). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as R311W. ClinVar contains an entry for this variant (Variation ID: 18358). 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 95%. Experimental studies have shown that this missense change affects CHRNE function (PMID: 9158150). This variant disrupts the p.Arg331 amino acid residue in CHRNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12417530). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 25, 2024	- -

Congenital myasthenic syndrome 4C Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1996

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 05, 2018

- -

Congenital myasthenic syndrome 4B Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Mar 01, 2023

The missense c.991C>T (p.Arg331Trp) variant in CHRNE gene has been reported in homozygous and compound heterozygous state in individualsaffected with congenital myasthenic syndrome (Ababneh NA, Al-Kurdi et al. 2020; Ealing J et al. 2002). The p.Arg331Trp variant has allele frequency 0.0004% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic (multiple submitters). The amino acid change p.Arg331Trp in CHRNE is predicted as conserved by PhyloP across 100 vertebrates. The amino acid Arg at position 331 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. -

Congenital myasthenic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 25, 2024

Variant summary: CHRNE c.991C>T (p.Arg331Trp) results in a non-conservative amino acid change located in the Neurotransmitter-gated ion-channel transmembrane domain (IPR006029) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 231394 control chromosomes. The variant, c.991C>T (aka. R311W) has been reported in the literature in multiple individuals affected with Congenital Myasthenic Syndrome (e.g. Ohno_1997, Ababneh_2020, Polavarapu_2024). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated decreased expression, and altered channel kinetics for the variant protein (Ohno_1997). In addition, a different missense affecting the same amino acid (R331Q) is classified as pathogenic by our lab oratory [ClinVar variation ID 641946]. The following publications have been ascertained in the context of this evaluation (PMID: 10496269, 32645605, 37721175). ClinVar contains an entry for this variant (Variation ID: 18358). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D;.
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.8	H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.7	D;.;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.94		Loss of disorder (P = 0.0189);Loss of disorder (P = 0.0189);.;
MVP		0.96
MPC		0.71
ClinPred		1.0	D
GERP RS		-0.00084
Varity_R		0.92
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121909515; hg19: chr17-4802804;