ClinVar Genomic variation as it relates to human health
NM_001005273.3(CHD3):c.3505C>T (p.Arg1169Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001005273.3(CHD3):c.3505C>T (p.Arg1169Trp)
Variation ID: 549741 Accession: VCV000549741.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7903281 (GRCh38) [ NCBI UCSC ] 17: 7806599 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Nov 3, 2018 Apr 15, 2024 Apr 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005273.3:c.3505C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005273.1:p.Arg1169Trp missense NM_001005271.3:c.3682C>T NP_001005271.2:p.Arg1228Trp missense NM_005852.4:c.3505C>T NP_005843.2:p.Arg1169Trp missense NC_000017.11:g.7903281C>T NC_000017.10:g.7806599C>T - Protein change
- R1169W, R1228W
- Other names
- p.Arg1169Trp
- Canonical SPDI
- NC_000017.11:7903280:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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CHD3 | - | - |
GRCh38 GRCh37 |
362 | 435 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
no assertion criteria provided
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May 3, 2018 | RCV000714497.3 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 10, 2023 | RCV000722153.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 25, 2021 | RCV001266103.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2022 | RCV001799697.11 |
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
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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
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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
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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. |
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Pathogenic
(Feb 19, 2019)
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criteria provided, single submitter
Method: curation
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Snijders Blok-Campeau syndrome
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000930102.1
First in ClinVar: Aug 05, 2019 Last updated: Aug 05, 2019 |
Comment:
This variant is interpreted as a Pathogenic for Snijders Blok-Campeau syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or … (more)
This variant is interpreted as a Pathogenic for Snijders Blok-Campeau syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6-Strong : Multiple de novo occurrences, but without confirmation of paternity and maternity (PMID:30397230; 29463886). PM1-supporting : PM1 downgraded in strength to Supporting. PP2 : Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease. PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS4-Moderate : PS4 downgraded in strength to Moderate (PMID:30397230; 29463886). (less)
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Snijders Blok-Campeau syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140276.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Snijders Blok-Campeau syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002572912.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: NA). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000549741). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Macrocephaly (present) , Intellectual disability (present) , Hypertelorism (present) , Epicanthus (present) , Low-set ears (present) , Strabismus (present) , Ptosis (present) , Bulbous nose … (more)
Macrocephaly (present) , Intellectual disability (present) , Hypertelorism (present) , Epicanthus (present) , Low-set ears (present) , Strabismus (present) , Ptosis (present) , Bulbous nose (present) , Anteverted nares (present) (less)
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Pathogenic
(Aug 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001444275.3
First in ClinVar: Nov 21, 2020 Last updated: Feb 07, 2023 |
Comment:
The c.3682C>T (p.R1228W) alteration is located in coding exon 23 of the CHD3 gene. This alteration results from a C to T substitution at nucleotide … (more)
The c.3682C>T (p.R1228W) alteration is located in coding exon 23 of the CHD3 gene. This alteration results from a C to T substitution at nucleotide position 3682, causing the arginine (R) at amino acid position 1228 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration (also referred to as p.R1169W in the literature) has been reported de novo in a patient from a cohort of individuals with developmental disorders (DDD, 2017) and in another patient with speech disorder characterized as childhood apraxia of speech who was later found to have intellectual disability (Eising, 2018; Snijders Blok, 2018). This amino acid position is highly conserved in available vertebrate species. The p.R1228W amino acid is located in the SNF2-like ATPase/helicase domain, which consists of two subdomains; a helicase ATP-binding lobe and C-terminal lobe. The majority of mutations have been observed to cluster within or around this domain. This domain uses ATPase activity to provide energy for nucleosome remodeling (Snijders Blok, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002044001.2
First in ClinVar: Jan 01, 2022 Last updated: Mar 04, 2023 |
Comment:
Multiple pathogenic missense variants at this residue (p.R1228L and p.R1228P) have been reported at GeneDx association with a CHD3-related disorder; Not observed at significant frequency … (more)
Multiple pathogenic missense variants at this residue (p.R1228L and p.R1228P) have been reported at GeneDx association with a CHD3-related disorder; Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 28135719, 29463886, 30397230, 31785789, 27535533) (less)
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Pathogenic
(Apr 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Snijders Blok-Campeau syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV003915699.1
First in ClinVar: Apr 23, 2023 Last updated: Apr 23, 2023 |
Comment:
A heterozygous missense variant in Exon 23 of the CHD3 gene that results in the amino acid substitution of Tryptophan for Arginine at codon 1169 … (more)
A heterozygous missense variant in Exon 23 of the CHD3 gene that results in the amino acid substitution of Tryptophan for Arginine at codon 1169 (p.Arg1169Trp) was detected. The observed variant has previously been reported in patients affected with neurodevelopmental syndrome with macrocephaly and impaired speech and language [PMID:30397230, 29463886]. The p.Arg1169Trp variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2) and topmed databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Talipes equinovarus (present)
Age: 0-9 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Oct 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002822360.8
First in ClinVar: Jan 21, 2023 Last updated: Apr 15, 2024 |
Comment:
CHD3: PS2, PM2, PS4:Moderate, PP2, PP3
Number of individuals with the variant: 1
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Likely pathogenic
(May 03, 2018)
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no assertion criteria provided
Method: research
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Intellectual disability
Affected status: yes
Allele origin:
germline
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CHU Sainte-Justine Research Center, University of Montreal
Accession: SCV000787643.1
First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018 |
Observation 1: Observation 2: Observation 3: |
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Pathogenic
(Jun 24, 2019)
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no assertion criteria provided
Method: literature only
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SNIJDERS BLOK-CAMPEAU SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000854571.2
First in ClinVar: Dec 02, 2018 Last updated: Jun 27, 2019 |
Comment on evidence:
In a patient (proband 01) with Snijders Blok-Campeau syndrome (SNIBCPS; 618205), Eising et al. (2019) identified a de novo heterozygous c.3682C-T transition (c.3682C-T, ENST00000380358) in … (more)
In a patient (proband 01) with Snijders Blok-Campeau syndrome (SNIBCPS; 618205), Eising et al. (2019) identified a de novo heterozygous c.3682C-T transition (c.3682C-T, ENST00000380358) in the CHD3 gene, resulting in an arg1228-to-trp (R1228W) substitution at a highly conserved residue in the helicase domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project, Exome Variant Server, and ExAC databases. Functional studies of the variant and studies of patient cells were not performed. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. | Eising E | Molecular psychiatry | 2019 | PMID: 29463886 |
CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. | Snijders Blok L | Nature communications | 2018 | PMID: 30397230 |
Prevalence and architecture of de novo mutations in developmental disorders. | Deciphering Developmental Disorders Study | Nature | 2017 | PMID: 28135719 |
Text-mined citations for rs1567861468 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.