Submissions for variant NM_001271.4(CHD2):c.4909C>T (p.Arg1637Ter)

dbSNP: rs864309547

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479724	SCV000568799	pathogenic	not provided	2022-10-16	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); This variant is associated with the following publications: (PMID: 25783594, 25418537, 25363768, 28191890, 26677509, 31332282, 28714951, 31981491, 31785789, 34859793)
Invitae	RCV000202631	SCV001236781	pathogenic	Developmental and epileptic encephalopathy 94	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1637*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with childhood-onset epileptic encephalopathy (PMID: 25783594). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 218398). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266033	SCV001444205	pathogenic	Inborn genetic diseases	2019-03-28	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000202631	SCV001984833	pathogenic	Developmental and epileptic encephalopathy 94	2020-07-31	criteria provided, single submitter	clinical testing	This nonsense variant found in exon 38 of 39 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a de novo change in an individual affected with childhood-onset epileptic encephalopathy (PMID: 25783594) as well as in individuals with intellectual disability and/or autism spectrum disorders (PMID: 25363768, 25418537, 28191890, 31332282). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.4909C>T (p.Arg1637Ter) variant is classified as Pathogenic.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV002287393	SCV002578161	pathogenic	not specified	2022-09-27	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000202631	SCV003845969	pathogenic	Developmental and epileptic encephalopathy 94		criteria provided, single submitter	clinical testing	A Heterozygous Splice site region, Nonsense variant c.4909C>T in Exon 38 of the CHD2 gene that results in the amino acid substitution p.Arg1637* was identified. The observed variant has a minor allele frequency of 0.000% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 218398 as of 2023-01-07). This nonsense variant found in exon 38 of 39 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a de novo change in an individual affected with childhood-onset epileptic encephalopathy (Galizia, Elizabeth C et al., 2015) as well as in individuals with intellectual disability and/or autism spectrum disorders (Kosmicki, Jack A et al., 2017; Du, Yaoqiang et al., 2020). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
PreventionGenetics, part of Exact Sciences	RCV003897438	SCV004713122	pathogenic	CHD2-related condition	2024-01-05	criteria provided, single submitter	clinical testing	The CHD2 c.4909C>T variant is predicted to result in premature protein termination (p.Arg1637*). This variant has been reported as de novo in a patient with idiopathic photosensitive occipital epilepsy and in several patients with autism spectrum disorder (Galizia et al. 2015. PubMed ID: 25783594; Table S2, Iossifov et al. 2014. PubMed ID: 25363768; Table S1, O'Roak et al. 2014. PubMed ID: 25418537; Table S1, Kosmicki et al. 2017. PubMed ID: 28191890). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in CHD2 are expected to be pathogenic. This variant is interpreted as pathogenic.