ClinVar Miner

Submissions for variant NM_000744.6(CHRNA4):c.851C>T (p.Ser284Leu) (rs28931591)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720920 SCV000851804 pathogenic Seizures 2016-09-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
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
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).
GeneReviews RCV000019052 SCV000057845 pathologic Epilepsy, nocturnal frontal lobe, type 1 2012-09-20 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000692832 SCV000820675 pathogenic Autosomal dominant nocturnal frontal lobe epilepsy 2018-10-09 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, and 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.
OMIM RCV000019052 SCV000039339 pathogenic Epilepsy, nocturnal frontal lobe, type 1 2011-08-01 no assertion criteria provided literature only

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