Submissions for variant NM_000742.4(CHRNA2):c.503C>T (p.Thr168Met)

gnomAD frequency: 0.00001  dbSNP: rs766076722

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186864	SCV000240435	uncertain significance	not provided	2022-02-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Campbell2015[Thesis])
Labcorp Genetics (formerly Invitae), Labcorp	RCV001351596	SCV001546086	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy	2024-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 168 of the CHRNA2 protein (p.Thr168Met). This variant is present in population databases (rs766076722, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CHRNA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 204959). 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) performed at Invitae indicates that this missense variant is expected to disrupt CHRNA2 protein function with a positive predictive value of 80%. 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.
Ambry Genetics	RCV002336492	SCV002644379	likely benign	Inborn genetic diseases	2021-07-14	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.
Revvity Omics, Revvity	RCV003485552	SCV004235073	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy 4	2023-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700569	SCV005204439	uncertain significance	not specified	2024-06-11	criteria provided, single submitter	clinical testing	Variant summary: CHRNA2 c.503C>T (p.Thr168Met) results in a non-conservative amino acid change located in the Neurotransmitter-gated ion-channel ligand-binding domain (IPR006202) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251444 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.503C>T in individuals affected with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy 4 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 204959). Based on the evidence outlined above, the variant was classified as uncertain significance.