rs28931591
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000744.7(CHRNA4):c.851C>T(p.Ser284Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S284S) has been classified as Likely benign.
Frequency
Consequence
NM_000744.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHRNA4 | NM_000744.7 | c.851C>T | p.Ser284Leu | missense_variant | 5/6 | ENST00000370263.9 | NP_000735.1 | |
CHRNA4 | NM_001256573.2 | c.323C>T | p.Ser108Leu | missense_variant | 5/6 | NP_001243502.1 | ||
CHRNA4 | NR_046317.2 | n.1060C>T | non_coding_transcript_exon_variant | 5/6 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 99
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant nocturnal frontal lobe epilepsy 1 Pathogenic:4Other:1
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Nov 16, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Apr 13, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | 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 - |
Autosomal dominant nocturnal frontal lobe epilepsy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 06, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CHRNA4 function (PMID: 19020039, 19237585, 22036597). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 17500). This variant is also known as c.755C>T (p.Ser252Leu). 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 not present in population databases (gnomAD no frequency). 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). - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2016 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 11, 2014 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at