ClinVar Miner

Submissions for variant NM_001271.4(CHD2):c.574A>G (p.Lys192Glu) (rs377701152)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000434807 SCV000536519 uncertain significance not provided 2017-01-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CHD2 gene. The K192E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The K192E variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K192E 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000541668 SCV000654350 uncertain significance Epileptic encephalopathy, childhood-onset 2017-04-22 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 192 of the CHD2 protein (p.Lys192Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs377701152, ExAC 0.001%) but has not been reported in the literature in individuals with a CHD2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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