ClinVar Miner

Submissions for variant NM_000744.7(CHRNA4):c.851C>T (p.Ser284Leu) (rs28931591)

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Total submissions: 7
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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).
Invitae RCV000692832 SCV000820675 pathogenic Autosomal dominant nocturnal frontal lobe epilepsy 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 284 of the CHRNA4 protein (p.Ser284Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in several families (PMID: 10563623, 12887446, 14623738) and identified as de novo in individuals affected with ADNFLE (PMID: 10939581, 22118295). This variant is also known as c.755C>T (p.Ser252Leu) in the literature. ClinVar contains an entry for this variant (Variation ID: 17500). Experimental studies have shown that this missense change increases the binding activity of the receptor (PMID:19237585, 22036597). A transgenic rat carrying this variant has similar clinical features to those of human ADNFLE (PMID: 19020039). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000720920 SCV000851804 pathogenic Seizures 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 Epilepsy, nocturnal frontal lobe, type 1 2021-04-13 criteria provided, single submitter clinical testing
OMIM RCV000019052 SCV000039339 pathogenic Epilepsy, nocturnal frontal lobe, type 1 2011-08-01 no assertion criteria provided literature only
GeneReviews RCV000019052 SCV000057845 pathologic Epilepsy, nocturnal frontal lobe, type 1 2012-09-20 no assertion criteria provided curation Converted during submission to Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000019052 SCV000804969 likely pathogenic Epilepsy, nocturnal frontal lobe, type 1 2016-11-16 no assertion criteria provided clinical testing

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