Submissions for variant NM_001271.4(CHD2):c.3802C>T (p.Arg1268Cys)

dbSNP: rs2054200789

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001345050	SCV001539147	uncertain significance	Developmental and epileptic encephalopathy 94	2020-06-21	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals with CHD2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 1268 of the CHD2 protein (p.Arg1268Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine.
New York Genome Center	RCV001345050	SCV001622827	likely pathogenic	Developmental and epileptic encephalopathy 94	2020-05-15	criteria provided, single submitter	clinical testing	The de novo c.3802C>T (p.Arg1268Cys) variant identified in the CHD gene substitutes a well conserved Arginine for Cystine at amino acid 1268/1829 (coding exon 30/39). This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Deleterious (Provean; score: -3.83) and Damaging (SIFT; score: 0.04) to the function of the canonical transcript. This variant is absent from ClinVar, although a different amino acid change at the same amino acid is reported there as a Variant of Uncertain Significance (p.Arg1268His; VarID:648951). To our current knowledge this variant has not been reported in affected individuals in the literature. The p.Arg1268 residue is not within a mapped domain of CHD2 (UniProtKB: O14647). While most pathogenic variants previously described in CHD2 are nonsense, frameshift, or missense variants within the Helicase domains, more recently missense variants outside of mapped domains have been described in individuals with CHD2-associated seizure disorders. Chen et.al (2020)identified a male with a de novo p.Arg1707Gln variant (patient 1), and twins with a p.Met1744Ile variant (patients 6,7) who inherited the variant from their father who had seizures in infancy [PMID:31677157]. Hoelz et.al (2020) also reported a Pathogenic/Likely Pathogenic p.Gly1277Ser variant in CHD2 in an individual with myoclonic epilepsy, although additional clinical information was not available for that individual [PMID:31554424]. Given its presence de novo in the affected individual, absence in population databases, and in silico algorithms predicting a damaging effect, the c.3802C>T (p.Arg1268Cys) variant identified in the CHD2 gene is reported here as Likely Pathogenic.
GeneDx	RCV005005192	SCV005629007	uncertain significance	not provided	2024-07-18	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