Submissions for variant NM_000080.4(CHRNE):c.488C>T (p.Ser163Leu)

dbSNP: rs121909516

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429916	SCV000521107	likely pathogenic	not provided	2023-06-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (failure of protein product to assemble with the alpha subunit of the acetylcholine receptor) (Ohno et al., 1996); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.S143L; This variant is associated with the following publications: (PMID: 8755487, 32403337, 33199334, 37091313)
Invitae	RCV000707387	SCV000836483	likely pathogenic	Congenital myasthenic syndrome 4A	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 163 of the CHRNE protein (p.Ser163Leu). This variant is present in population databases (rs121909516, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 8755487). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as S143L. ClinVar contains an entry for this variant (Variation ID: 18360). 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. Experimental studies have shown that this missense change affects CHRNE function (PMID: 8755487). 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	RCV001004608	SCV001163794	likely pathogenic	Congenital myasthenic syndrome 4C		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000429916	SCV002022553	likely pathogenic	not provided	2021-06-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000707387	SCV004217768	likely pathogenic	Congenital myasthenic syndrome 4A	2023-10-31	criteria provided, single submitter	clinical testing
OMIM	RCV000020028	SCV000040326	pathogenic	Congenital myasthenic syndrome 4B	1996-07-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000429916	SCV001548908	uncertain significance	not provided		flagged submission	clinical testing	The CHRNE p.S163L variant was identified in the literature in two compound heterozygous siblings with congenital myasthenic syndrome (Ohno_1996_PMID:8755487). The variant was identified in dbSNP (ID: rs121909516) and ClinVar (classified as uncertain significance by Invitae and Illumina; as likely pathogenic by GeneDx and Baylor Genetics; and as pathogenic by OMIM). The variant was identified in control databases in 74 of 281378 chromosomes at a frequency of 0.0002630, and was observed at the highest frequency in the European (non-Finnish) population in 60 of 127756 chromosomes (freq: 0.0004696) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.S163 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional analysis of the p.S163L variant demonstrates reduced protein expression compared to wildtype and impaired acetylcholine receptor subunit assembly (Ohno_1996_PMID:8755487). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome, Splice AI genome) 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.
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319975	SCV004023417	likely pathogenic	Tip-toe gait	2020-11-12	no assertion criteria provided	clinical testing