Submissions for variant NM_000080.4(CHRNE):c.1434C>A (p.Tyr478Ter)

gnomAD frequency: 0.00002  dbSNP: rs763943642

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760410	SCV000890287	likely pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing	The Y478X variant in the CHRNE gene has been reported previously (as Y458X, due to alternate nomenclature) in the heterozygous state in two individuals from one family with AChR deficiency syndrome (Ealing et al., 2002). Functional assessment of the Y478X variant displayed reduction of surface localization of AChR compared to wild type (Ealing et al., 2002). This variant is predicted to cause loss of normal protein function through protein truncation. The Y478X variant is not observed in large population cohorts (Lek et al., 2016). We interpret Y478X as a likely pathogenic variant.
Invitae	RCV002533835	SCV003443726	uncertain significance	Congenital myasthenic syndrome 4A	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr478*) in the CHRNE gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the CHRNE protein. 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 premature translational stop signal has been observed in individual(s) with CHRNE-related conditions and/or clinical features of autosomal recessive congenital myasthenic syndrome (PMID: 12417530; Invitae). This variant is also known as p.Tyr458*. ClinVar contains an entry for this variant (Variation ID: 620130). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CHRNE function (PMID: 12417530). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.