Submissions for variant NM_000080.4(CHRNE):c.992G>A (p.Arg331Gln)

dbSNP: rs760022829

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000795308	SCV000934763	likely pathogenic	Congenital myasthenic syndrome 4A	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 331 of the CHRNE protein (p.Arg331Gln). 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: 12417530). 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 p.Arg311Gln. ClinVar contains an entry for this variant (Variation ID: 641946). 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 does not substantially affect CHRNE function (PMID: 12417530). This variant disrupts the p.Arg331 amino acid residue in CHRNE. Other variant(s) that disrupt this residue have been observed in individuals with CHRNE-related conditions (PMID: 9158150), which suggests that this may be a clinically significant amino acid residue. 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	RCV001328997	SCV001520277	pathogenic	Congenital myasthenic syndrome 4B	2019-12-12	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814235	SCV001755224	likely pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001835960	SCV004121890	pathogenic	Congenital myasthenic syndrome	2023-10-03	criteria provided, single submitter	clinical testing	Variant summary: CHRNE c.992G>A (p.Arg331Gln) results in a conservative amino acid change located in the Neurotransmitter-gated ion-channel transmembrane domain (IPR006029) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 230936 control chromosomes. c.992G>A has been reported in the literature in multiple individuals affected with Congenital Myasthenic Syndrome, either in trans along with second pathogenic variants or at a homozygous state (examples, Ealing_2002, Faber_2009). Additionally, at least one variant at the Arg331 residue has been reported in patients with Congenital Myasthenic Syndrome (p.R331W, Likely Pathogenic in ClinVar), suggesting that this codon may be functionally important. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12417530, 19544078). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000795308	SCV004214241	pathogenic	Congenital myasthenic syndrome 4A	2023-07-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001835960	SCV002093402	likely pathogenic	Congenital myasthenic syndrome	2020-12-01	no assertion criteria provided	clinical testing