ClinVar Miner

Submissions for variant NM_000744.7(CHRNA4):c.839C>T (p.Ser280Phe) (rs121909580)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487099 SCV000567702 pathogenic not provided 2015-09-11 criteria provided, single submitter clinical testing The S280F missense change (reported as S248F due to the use of alternate nomenclature) was initially found to segregate with ADNFLE in 21 affected individuals spanning multiple generations of a large family (Steinlein et al., 1995). It has subsequently been reported to segregate with ADNFLE in multiple other large families (Steinlein et al., 2011). The S280F variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. S280F is a non-conservative amino acid substitution that occurs at a conserved position in the second transmembrane domain of the protein, which forms the wall of the ionic pore. Functional studies in Xenopus oocytes suggest that S280F is a gain-of-function variant that results in increased sensitivity of the receptor to acetylcholine (Steinlein et al., 2011). Therefore, S280F in CHRNA4 is interpreted to be a pathogenic variant.
Invitae RCV001206285 SCV001377586 pathogenic Autosomal dominant nocturnal frontal lobe epilepsy 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 280 of the CHRNA4 protein (p.Ser280Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in a family (PMID: 7550350) and in several unrelated individuals (PMID: 22036597). This variant is also known as S248F in the literature. ClinVar contains an entry for this variant (Variation ID: 17498). This variant has been reported to affect CHRNA4 protein function (PMID: 19020039, 22036597, 19237585). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000019050 SCV000039337 pathogenic Epilepsy, nocturnal frontal lobe, type 1 2008-09-09 no assertion criteria provided literature only
GeneReviews RCV000019050 SCV000057844 pathologic Epilepsy, nocturnal frontal lobe, type 1 2012-09-20 no assertion criteria provided curation Converted during submission to Pathogenic.

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