ClinVar Miner

Submissions for variant NM_001271.4(CHD2):c.4061G>A (p.Arg1354Lys) (rs370160870)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000651624 SCV000896497 uncertain significance Epileptic encephalopathy, childhood-onset 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000482010 SCV000571499 uncertain significance not provided 2016-08-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CHD2 gene. The R1354K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1354K variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R1354K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. However, 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 RCV000651624 SCV000773478 uncertain significance Epileptic encephalopathy, childhood-onset 2018-02-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 1354 of the CHD2 protein (p.Arg1354Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs370160870, ExAC 0.004%). This variant has not been reported in the literature in individuals with CHD2-related disease. ClinVar contains an entry for this variant (Variation ID: 422112). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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