Submissions for variant NM_000080.4(CHRNE):c.1168C>T (p.Arg390Trp)

gnomAD frequency: 0.00005  dbSNP: rs140763858

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000272936	SCV000341859	uncertain significance	not provided	2016-06-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816705	SCV000957224	uncertain significance	Congenital myasthenic syndrome 4A	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 390 of the CHRNE protein (p.Arg390Trp). This variant is present in population databases (rs140763858, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CHRNE-related conditions. ClinVar contains an entry for this variant (Variation ID: 287912). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CHRNE protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000272936	SCV003830637	uncertain significance	not provided	2023-09-12	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000272936	SCV004229530	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools disagree on the variant's effect on normal protein function.
Natera, Inc.	RCV001274712	SCV001459092	uncertain significance	Congenital myasthenic syndrome	2019-10-28	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000272936	SCV001551023	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CHRNE p.Arg390Trp variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs140763858) and ClinVar (classified as a VUS by EGL Genetics and Invitae). The variant was also identified in control databases in 17 of 237074 chromosomes at a frequency of 0.000072 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 15122 chromosomes (freq: 0.000198), European (non-Finnish) in 12 of 106590 chromosomes (freq: 0.000113) and South Asian in 2 of 30222 chromosomes (freq: 0.000066), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish) or Other populations. The p.Arg390 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.