Submissions for variant NM_000744.7(CHRNA4):c.274G>C (p.Glu92Gln)

gnomAD frequency: 0.00029  dbSNP: rs146651027

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186963	SCV000240534	benign	not specified	2017-10-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654308	SCV000776198	likely benign	Autosomal dominant nocturnal frontal lobe epilepsy	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002314694	SCV000849052	likely benign	Inborn genetic diseases	2018-08-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000767933	SCV000898609	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy 1	2018-08-27	criteria provided, single submitter	clinical testing	CHRNA4 NM_000744.6 exon 4 c.274G>A (p.Glu92Gln): This variant has not been reported in the literature and is present in 0.06% (75/119670) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/20-61987436-C-G). This variant is present in ClinVar (Variation ID:205043). Evolutionary conservation of this residue suggests that this may impact the protein, but computational predictive tools for this variant are conflicting. Of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV001090874	SCV001246636	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	CHRNA4: PP3, BS1
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000477750	SCV003919799	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy 1; Tobacco addiction, susceptibility to	2021-11-11	criteria provided, single submitter	clinical testing	CHRNA4 NM_000744.6 exon 4 c.274G>A (p.Glu92Gln): This variant has not been reported in the literature and is present in 0.06% (75/119670) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/20-61987436-C-G). This variant is present in ClinVar (Variation ID:205043). Evolutionary conservation of this residue suggests that this may impact the protein, but computational predictive tools for this variant are conflicting. Of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477750	SCV000536811	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy 1; Tobacco addiction, susceptibility to	2016-07-03	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003947567	SCV004763863	likely benign	CHRNA4-related disorder	2023-02-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).