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

gnomAD frequency: 0.00003  dbSNP: rs121912243

Total submissions: 6

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
Invitae	RCV000654323	SCV000776213	likely benign	Autosomal dominant nocturnal frontal lobe epilepsy	2023-11-27	criteria provided, single submitter	clinical testing
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844035	SCV002103555	uncertain significance	not specified	2022-02-10	criteria provided, single submitter	clinical testing	Variant summary: CHRNA4 c.442C>T (p.Arg148Trp) results in a non-conservative amino acid change located in the Neurotransmitter-gated ion-channel ligand-binding domain (IPR006202) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250556 control chromosomes. This frequency does not allow conclusions about variant significance. c.442C>T has been reported in the literature as a heterozygous de-novo variant classified as "uncertain" in one individual affected with a combined co-occurring neurological manifestation of multifocal dystonia undergoing diagnostic exome sequencing (DES) (example, Powis_2020). However, this individual also harbored a second de-novo heterozygous variant in the NACC1 gene, c.892C>T (p.R298W) that the authors report as "likely pathogenic" without evidence for independent evaluation. Due to this finding of potentially relevant findings in multiple genes, this report does not provide unequivocal conclusions about association of the variant with Epilepsy, Nocturnal Frontal Lobe, Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign, n=1; VUS, n=2). None of the submitters cite the evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Psychiatry Genetics Yale University	RCV000084614	SCV000116750	not provided	Tobacco use disorder		no assertion provided	not provided