ClinVar Miner

Submissions for variant NM_001271.4(CHD2):c.1769A>G (p.Asn590Ser) (rs373555806)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494206 SCV000582035 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CHD2 gene. The N590S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N590S variant is observed in 1/56928 (0.002%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N590S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably 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 RCV000557924 SCV000654314 uncertain significance Epileptic encephalopathy, childhood-onset 2017-01-31 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 590 of the CHD2 protein (p.Asn590Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs373555806, ExAC 0.002%) 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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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