Submissions for variant NM_000744.7(CHRNA4):c.1106G>A (p.Arg369Gln)

gnomAD frequency: 0.00007  dbSNP: rs200007766

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481191	SCV000567082	uncertain significance	not provided	2017-05-12	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CHRNA4 gene. The R369Q variant has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R369Q variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R369Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution alters a poorly conserved position and is not predicted to occur within the transmembrane region of the protein, where the vast majority of pathogenic missense variants have been identified in association with epilepsy (Steinlein et al., 2010). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001213400	SCV001385029	likely benign	Autosomal dominant nocturnal frontal lobe epilepsy	2024-09-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001334565	SCV001527445	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy 1	2018-04-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute of Human Genetics, University of Leipzig Medical Center	RCV001334565	SCV002549830	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy 1	2022-06-21	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM1_SUP
Ambry Genetics	RCV002436532	SCV002745234	likely benign	Inborn genetic diseases	2020-09-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005239065	SCV005884234	uncertain significance	not specified	2024-12-10	criteria provided, single submitter	clinical testing	Variant summary: CHRNA4 c.1106G>A (p.Arg369Gln) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 249100 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHRNA4 causing Epilepsy, Nocturnal Frontal Lobe, Type 1, allowing no conclusion about variant significance. c.1106G>A has been reported in the literature in at least one individual affected with amyotrophic lateral sclerosis (e.g. Lattante_2020) . This report does not provide unequivocal conclusions about association of the variant with Epilepsy, Nocturnal Frontal Lobe, Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 419347). Based on the evidence outlined above, the variant was classified as uncertain significance.