ClinVar Miner

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

dbSNP: rs121909580
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Total submissions: 5
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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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001206285 SCV001377586 pathogenic Autosomal dominant nocturnal frontal lobe epilepsy 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 280 of the CHRNA4 protein (p.Ser280Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomaldominant nocturnal frontal lobe epilepsy (ADNFLE) (PMID: 7550350, 22036597). It has also been observed to segregate with disease in related individuals. This variant is also known as S248F. ClinVar contains an entry for this variant (Variation ID: 17498). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV000019050 SCV002576430 pathogenic Autosomal dominant nocturnal frontal lobe epilepsy 1 2022-08-22 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PS3, PS4, PP1_STR, PM2_SUP
Revvity Omics, Revvity RCV000019050 SCV003818685 pathogenic Autosomal dominant nocturnal frontal lobe epilepsy 1 2022-08-10 criteria provided, single submitter clinical testing
OMIM RCV000019050 SCV000039337 pathogenic Autosomal dominant nocturnal frontal lobe epilepsy 1 2008-09-09 no assertion criteria provided literature only

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