ClinVar Miner

Submissions for variant NM_000744.6(CHRNA4):c.1726G>C (p.Asp576His) (rs537904499)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186958 SCV000240529 uncertain significance not specified 2016-04-27 criteria provided, single submitter clinical testing The D576H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports D576H was observed in 2/172 (1.2%) alleles from individuals of Bengali background, indicating it may be a rare (benign) variant in this population. The D576H 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. This substitution occurs at a position that is conserved in mammals. However, 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). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000654336 SCV000776226 likely benign Autosomal dominant nocturnal frontal lobe epilepsy 2017-11-19 criteria provided, single submitter clinical testing

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