Submissions for variant NM_001271.4(CHD2):c.2425C>T (p.Arg809Ter)

dbSNP: rs146691368

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000579050	SCV000681270	pathogenic	not provided	2022-09-30	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000651631	SCV000773485	pathogenic	Developmental and epileptic encephalopathy 94	2023-04-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 489275). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with CHD2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg809*) in the CHD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHD2 are known to be pathogenic (PMID: 23708187, 24207121).
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000651631	SCV004177006	pathogenic	Developmental and epileptic encephalopathy 94	2023-09-08	criteria provided, single submitter	clinical testing	The CHD2 c.2425C>T (p.Arg809Ter) variant, to our knowledge, has not been reported in the medical literature in an individual with developmental and epileptic encephalopathy but has been reported in the ClinVar database as a germline pathogenic variant by two submitters. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon, which is predicted to lead to nonsense mediated decay. Additionally, several other variants that introduce premature termination codons occur downstream of this variant and are considered pathogenic (Chen J et al., PMID: 31677157). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.