ClinVar Miner

Submissions for variant NM_000744.7(CHRNA4):c.442C>T (p.Arg148Trp) (rs121912243)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186922 SCV000240493 uncertain significance not provided 2013-09-25 criteria provided, single submitter clinical testing p.Arg148Trp (CGG>TGG): c.442 C>T: The Arg148Trp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged Tryptophan residue at a position that is conserved across species. In silico analysis predicts this variant may be damaging to the protein structure/function. However, this amino acid substitution does not occur within the transmembrane region of the protein, where the vast majority of pathogenic missense mutations have been identified in association with epilepsy (Steinlein et al., 2010). The Arg148Trp variant may be a benign variant or a disease-associated mutation, as mutations in CHRNA4 demonstrate incomplete penetrance (Hirose and Kurahashi, 2012). This variant has been observed to be paternally inherited. The variant is found in EPILEPSY panel(s).
Ambry Genetics RCV000190688 SCV000244129 uncertain significance Inborn genetic diseases 2017-02-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Invitae RCV000654323 SCV000776213 uncertain significance Autosomal dominant nocturnal frontal lobe epilepsy 2019-06-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 148 of the CHRNA4 protein (p.Arg148Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121912243, ExAC 0.009%). This variant has not been reported in the literature in individuals with CHRNA4-related disease. ClinVar contains an entry for this variant (Variation ID: 98324). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory,Koc University RCV001095406 SCV001251114 likely benign Amyotrophic lateral sclerosis 2020-03-31 criteria provided, single submitter research
Psychiatry Genetics Yale University RCV000084614 SCV000116750 not provided Tobacco use disorder no assertion provided not provided

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