Submissions for variant NM_000748.3(CHRNB2):c.1046T>C (p.Met349Thr)

gnomAD frequency: 0.00010  dbSNP: rs141735618

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723869	SCV000230965	uncertain significance	not provided	2014-06-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000723869	SCV000571079	uncertain significance	not provided	2016-08-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CHRNB2 gene. The M349T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M349T variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The M349T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. Furthermore, this amino acid substitution 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). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001039180	SCV001202696	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 349 of the CHRNB2 protein (p.Met349Thr). This variant is present in population databases (rs141735618, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CHRNB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 197695). 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 CHRNB2 protein function. 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	RCV002399637	SCV002709452	likely benign	Inborn genetic diseases	2018-08-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
PreventionGenetics, part of Exact Sciences	RCV003416096	SCV004116379	uncertain significance	CHRNB2-related condition	2023-04-24	criteria provided, single submitter	clinical testing	The CHRNB2 c.1046T>C variant is predicted to result in the amino acid substitution p.Met349Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-154544345-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000723869	SCV004701363	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	CHRNB2: PP2, PP3
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251720	SCV001427461	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535577	SCV001749566	not provided	Autosomal dominant nocturnal frontal lobe epilepsy 3		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-17-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.