ClinVar Miner

Submissions for variant NM_000748.3(CHRNB2):c.923T>C (p.Val308Ala)

dbSNP: rs281865070
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000430538 SCV000515823 likely pathogenic not provided 2022-07-28 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: V308A increases the sensitivity to acetylcholine and has a gain of function effect (Hoda et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12942156, 24395520, 22036597, 28102150, 28717674, 28488083, 26309560, 33284031, 19383498, 26147798, 32347641, 20301348, 26072248, 25717303, 33924731, 25969754, 31324802, 18456869)
Invitae RCV001382226 SCV001580898 pathogenic Autosomal dominant nocturnal frontal lobe epilepsy 2023-12-08 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 308 of the CHRNB2 protein (p.Val308Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of nocturnal frontal lobe epilepsy (PMID: 18456869). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41035). 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 not expected to disrupt CHRNB2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CHRNB2 function (PMID: 18456869). For these reasons, this variant has been classified as Pathogenic.

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