ClinVar Miner

Submissions for variant NM_000744.6(CHRNA4):c.1667C>G (p.Pro556Arg) (rs77345643)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523978 SCV000621122 uncertain significance not provided 2017-09-26 criteria provided, single submitter clinical testing The P556R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P556R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The P556R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Additionally, this amino acid substitution is not predicted to occur within the transmembrane region of the protein, where the vast majority of pathogenic missense variants have been identified in association with epilepsy (Steinlein et al., 2010). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000523978 SCV000821668 likely benign not provided 2018-10-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764254 SCV000895259 uncertain significance Epilepsy, nocturnal frontal lobe, type 1; Tobacco addiction, susceptibility to 2018-10-31 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000767930 SCV000898606 uncertain significance Epilepsy, nocturnal frontal lobe, type 1 2018-07-31 criteria provided, single submitter clinical testing CHRNA4 NM_000744.6 exon 5 p.Pro556Arg (c.1667C>G): This variant has not been reported in the literature but is present in 1/17128 East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs77345643). This variant is present in ClinVar (Variation ID:452325). This variant amino acid Arginine (Arg) is present in >30 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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