VCV000429658.22 - ClinVar

NM_001271.4(CHD2):c.2095C>T (p.Arg699Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001271.4(CHD2):c.2095C>T (p.Arg699Trp)

Variation ID: 429658 Accession: VCV000429658.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q26.1 15: 92967419 (GRCh38) [ NCBI UCSC ] 15: 93510649 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 2, 2017	Oct 20, 2024	May 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001271.4:c.2095C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001262.3:p.Arg699Trp	missense
NC_000015.10:g.92967419C>T
NC_000015.9:g.93510649C>T
NG_012826.2:g.72099C>T
LRG_1425:g.72099C>T
LRG_1425t1:c.2095C>T	LRG_1425p1:p.Arg699Trp

... more HGVS ... less HGVS

Protein change

R699W

Other names

Canonical SPDI

NC_000015.10:92967418:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA393907202 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CHD2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2090	2204

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 1, 2024	RCV000493748.15
Developmental and epileptic encephalopathy 94	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 16, 2023	RCV000505237.15
Inborn genetic diseases	no classifications from unflagged records (1)	no classifications from unflagged records	Jun 12, 2024	RCV000623592.12
Intellectual disability	Pathogenic (1)	criteria provided, single submitter	Sep 10, 2020	RCV001260660.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jul 12, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy 94 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV000890059.1 First in ClinVar: Sep 10, 2017 Last updated: Sep 10, 2017
Pathogenic (Sep 10, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability Affected status: yes Allele origin: de novo	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV001437752.1 First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020	Method: targeted next-gen sequencing
Pathogenic (Jun 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000582278.6 First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023	Comment: 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; … (more) 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; This variant is associated with the following publications: (PMID: 31785789, 33004838) (less)
Pathogenic (Aug 16, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Developmental and epileptic encephalopathy 94 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002167677.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 31785789‚ 33004838 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 699 of the CHD2 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 699 of the CHD2 protein (p.Arg699Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CHD2-related conditions (PMID: 31785789, 33004838; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.2134C>T (p.Arg712Trp) and 15:93510649C>T. ClinVar contains an entry for this variant (Variation ID: 429658). 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 expected to disrupt CHD2 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV005050647.5 First in ClinVar: Jun 17, 2024 Last updated: Oct 20, 2024	Comment: CHD2: PS2, PM2, PS4:Moderate, PP2, PP3 Number of individuals with the variant: 1
Likely pathogenic (Sep 30, 2016)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy 94 Affected status: yes Allele origin: de novo	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals Accession: SCV000599251.1 First in ClinVar: Sep 10, 2017 Last updated: Sep 10, 2017
Uncertain significance (Aug 11, 2016)	Flagged submission flagged submission (Ambry Variant Classification Scheme 2023) Method: clinical testing Reason: Older and outlier claim with insufficient supporting evidence Source: ClinGen	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000847520.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Comment: The p.R699W variant (also known as c.2095C>T), located in coding exon 16 of the CHD2 gene, results from a C to T substitution at nucleotide … (more) The p.R699W variant (also known as c.2095C>T), located in coding exon 16 of the CHD2 gene, results from a C to T substitution at nucleotide position 2095. The arginine at codon 699 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6495 samples (12990 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

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; This variant is associated with the following publications: (PMID: 31785789, 33004838)

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 699 of the CHD2 protein (p.Arg699Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CHD2-related conditions (PMID: 31785789, 33004838; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.2134C>T (p.Arg712Trp) and 15:93510649C>T. ClinVar contains an entry for this variant (Variation ID: 429658). 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 expected to disrupt CHD2 protein function. For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.R699W variant (also known as c.2095C>T), located in coding exon 16 of the CHD2 gene, results from a C to T substitution at nucleotide position 2095. The arginine at codon 699 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6495 samples (12990 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.	Wang T	Nature communications	2020	PMID: 33004838
Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders.	Turner TN	American journal of human genetics	2019	PMID: 31785789

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001271.4(CHD2):c.2095C>T (p.Arg699Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...