NM_001271.4(CHD2):c.2425C>T (p.Arg809Ter) AND Developmental and epileptic encephalopathy 94

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000651631.6

Allele description [Variation Report for NM_001271.4(CHD2):c.2425C>T (p.Arg809Ter)]

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

Gene:

CHD2:chromodomain helicase DNA binding protein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

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

HGVS:

NC_000015.10:g.92972337C>T
NG_012826.2:g.77017C>T
NM_001271.4:c.2425C>TMANE SELECT
NP_001262.3:p.Arg809Ter
LRG_1425t1:c.2425C>T
LRG_1425:g.77017C>T
LRG_1425p1:p.Arg809Ter
NC_000015.9:g.93515567C>T
NG_012826.1:g.77017C>T
NM_001271.3:c.2425C>T

Protein change:

R809*

Links:

dbSNP: rs146691368

NCBI 1000 Genomes Browser:

rs146691368

Molecular consequence:

NM_001271.4:c.2425C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Developmental and epileptic encephalopathy 94 (DEE94)
Synonyms:: Epileptic encephalopathy, childhood-onset
Identifiers:: MONDO: MONDO:0014150; MedGen: C3809278; Orphanet: 1942; Orphanet: 2382; OMIM: 615369

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000773485	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 26, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23708187, 24207121, 28492532
SCV004177006	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000773485

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 26, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004177006

Clinical Genomics Laboratory, Washington University in St. Louis

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 8, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.

Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, Malone S, Wallace G, Stanley T, Bye AM, Bleasel A, Howell KB, Kivity S, Mackay MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, et al.

Nat Genet. 2013 Jul;45(7):825-30. doi: 10.1038/ng.2646. Epub 2013 May 26.

PubMed [citation]

PMID:: 23708187
PMCID:: PMC3704157

De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.

Suls A, Jaehn JA, Kecskés A, Weber Y, Weckhuysen S, Craiu DC, Siekierska A, Djémié T, Afrikanova T, Gormley P, von Spiczak S, Kluger G, Iliescu CM, Talvik T, Talvik I, Meral C, Caglayan HS, Giraldez BG, Serratosa J, Lemke JR, Hoffman-Zacharska D, Szczepanik E, et al.

Am J Hum Genet. 2013 Nov 7;93(5):967-75. doi: 10.1016/j.ajhg.2013.09.017. Epub 2013 Oct 24.

PubMed [citation]

PMID:: 24207121
PMCID:: PMC3824114

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000773485.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genomics Laboratory, Washington University in St. Louis, SCV004177006.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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