Submissions for variant NM_001271.4(CHD2):c.1961A>G (p.Lys654Arg)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002846595	SCV003220530	uncertain significance	Developmental and epileptic encephalopathy 94	2022-07-11	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHD2 protein function. 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. This variant has not been reported in the literature in individuals affected with CHD2-related conditions. This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 654 of the CHD2 protein (p.Lys654Arg). This variant is not present in population databases (gnomAD no frequency).
GeneDx	RCV004774748	SCV005384266	uncertain significance	not provided	2024-01-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Neuberg Centre For Genomic Medicine, NCGM	RCV002846595	SCV005690635	uncertain significance	Developmental and epileptic encephalopathy 94	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.1961A>G (p.Lys654Arg) variant in gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Lys654Arg variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - Possibly damaging, SIFT – Damaging and Mutation Taster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on CHD2 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Lys at position 654 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).