Submissions for variant NM_000744.7(CHRNA4):c.851C>T (p.Ser284Leu)

dbSNP: rs28931591

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186931	SCV000240502	pathogenic	not provided	2014-06-11	criteria provided, single submitter	clinical testing	p.Ser284Leu (TCG>TTG): c.851 C>T in exon 5 of the CHRNA4 gene (NM_000744.5)The S284L missense change was initially found to segregate with autosomal dominant nocturnal frontal lobe epilepsy (NFLE) in four affected individuals in a Japanese family (Hirose et al., 1999). It has subsequently been identified as a de novo mutation in sporadic NFLE and in multiple families with autosomal dominant NFLE, and individuals with S284L are frequently reported to have drug-resistant seizures and/or intellectual disability (Phillips et al., 2001; Rozycka et al., 2003; Cho et al., 2003; Hwang et al., 2011). Functional studies in rats indicate that S284L results in abnormalities in GABAergic transmission (Zhu et al., 2008). S284L 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. It occurs at a highly conserved position within the 2nd transmembrane domain, which forms the wall of the ionic pore. Therefore, S284L is a pathogenic mutation. The variant is found in CHILD-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692832	SCV000820675	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy	2024-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 284 of the CHRNA4 protein (p.Ser284Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (PMID: 10563623, 10939581, 12887446, 14623738, 22118295). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.755C>T (p.Ser252Leu). ClinVar contains an entry for this variant (Variation ID: 17500). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CHRNA4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CHRNA4 function (PMID: 19020039, 19237585, 22036597). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002316197	SCV000851804	pathogenic	Inborn genetic diseases	2016-09-16	criteria provided, single submitter	clinical testing	The p.S284L pathogenic mutation (also known as c.851C>T), located in coding exon 5 of the CHRNA4 gene, results from a C to T substitution at nucleotide position 851. The serine at codon 284 is replaced by leucine, an amino acid with dissimilar properties. This pathogenic mutation segregated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in multiple families in the literature; some of these individuals had varying levels of intellectual disability and some were not responsive to seizure medication (Hirose S et al. Neurology, 1999 Nov;53:1749-53; Rozycka A et al. Epilepsia, 2003 Aug;44:1113-7; Cho YW et al. Arch. Neurol., 2003 Nov;60:1625-32). Functional studies found that this mutation results in faster desensitization when expressed in Xenopus oocytes, which is consistent with a loss of function mutation (Matsushima N et al. Epilepsy Res., 2002 Feb;48:181-6). In addition, rats with this mutation showed attenuation of synaptic and extrasynaptic GABAergic transmission with an NFLE phenotype (Zhu G et al. J. Neurosci., 2008 Nov;28:12465-76). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000019052	SCV001571374	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 1	2021-04-13	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000019052	SCV002557236	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. 0600 - Variant is located in the annotated neurotransmitter-gated ion-channel transmembrane domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in many individuals with nocturnal frontal lobe epilepsy (ClinVar, PMID: 10563623, PMID: 14623738). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in multi-generation families (PMID: 10563623, PMID: 14623738). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000019052	SCV000039339	pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 1	2011-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000019052	SCV000057845	not provided	Autosomal dominant nocturnal frontal lobe epilepsy 1		no assertion provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000019052	SCV000804969	likely pathogenic	Autosomal dominant nocturnal frontal lobe epilepsy 1	2016-11-16	no assertion criteria provided	clinical testing