Submissions for variant NM_000748.3(CHRNB2):c.859G>A (p.Val287Met)

dbSNP: rs74315291

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001091721	SCV001247914	pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216785	SCV001388597	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy	2023-06-27	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects CHRNB2 function (PMID: 11104662, 18456869, 22036597). 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 not expected to disrupt CHRNB2 protein function. ClinVar contains an entry for this variant (Variation ID: 17496). This missense change has been observed in individuals with autosomal dominant nocturnal frontal lobe epilepsy (PMID: 11104662, 17900292). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 287 of the CHRNB2 protein (p.Val287Met). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000019048	SCV002505576	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 3	2022-03-30	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS1, PM5_STR, PS3_MOD, PS4_MOD, PP1_MOD, PM2_SUP, PP3
Institute of Human Genetics, University of Leipzig Medical Center	RCV003493411	SCV004242495	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 1	2024-01-30	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM5_STR,PS3_MOD,PP1_MOD,PM2_SUP,PP3
Ambry Genetics	RCV004018644	SCV004924658	pathogenic	Inborn genetic diseases	2024-02-16	criteria provided, single submitter	clinical testing	The c.859G>A (p.V287M) alteration is located in exon 5 (coding exon 5) of the CHRNB2 gene. This alteration results from a G to A substitution at nucleotide position 859, causing the valine (V) at amino acid position 287 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported to segregate in two large families with varying severities of sleep-related hypermotor epilepsy and showed incomplete penetrance (Phillips, 2001; Díaz-Otero, 2008). Another alteration at the same codon, c.859G>C (p.V287L), has been described in a large family with nocturnal frontal lobe epilepsy (De Fusco, 2000). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). In two assays testing desensitization properties, this variant showed functionally altered results (Phillips, 2001; Hoda, 2008). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000019048	SCV000039335	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 3	2001-01-01	no assertion criteria provided	literature only