Published functional studies demonstrate a damaging effect on transcriptional regulation (Vulto-van Silfhout et al., 2014); 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: 28940898, 24726472, 33705764)
ClinVar Genomic variation as it relates to human health
NM_021008.4(DEAF1):c.670C>T (p.Arg224Trp)
Germline
Classification
Help
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)
Help
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_021008.4(DEAF1):c.670C>T (p.Arg224Trp)
Variation ID: 133293 Accession: VCV000133293.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 686992 (GRCh38) [ NCBI UCSC ] 11: 686992 (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 Feb 26, 2015 Oct 20, 2024 Feb 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_021008.4:c.670C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066288.2:p.Arg224Trp missense NM_001293634.1:c.664+919C>T intron variant NM_001367390.1:c.-57C>T 5 prime UTR NC_000011.10:g.686992G>A NC_000011.9:g.686992G>A NG_034156.2:g.25092C>T O75398:p.Arg224Trp - Protein change
- R224W
- Other names
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- Canonical SPDI
- NC_000011.10:686991:G:A
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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
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| DEAF1 | - | - |
GRCh38 GRCh38 GRCh37 |
728 | 891 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
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Dec 3, 2023 | RCV000119806.6 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV001310582.29 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002099567.2
First in ClinVar: Mar 04, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on transcriptional regulation (Vulto-van Silfhout et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Published functional studies demonstrate a damaging effect on transcriptional regulation (Vulto-van Silfhout et al., 2014); 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: 28940898, 24726472, 33705764) (less)
|
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Likely pathogenic
(Dec 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal dominant 24
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004242386.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
Criteria applied: PS2_MOD,PS4_MOD,PS3_SUP,PM2_SUP, PP3; 5x path in ClinVar but 6x in gnomad4.0
Clinical Features:
Focal impaired awareness seizure (present) , Autism (present) , Focal-onset seizure (present) , Bilateral tonic-clonic seizure with focal onset (present) , Hyperactivity (present) , Intellectual … (more)
Focal impaired awareness seizure (present) , Autism (present) , Focal-onset seizure (present) , Bilateral tonic-clonic seizure with focal onset (present) , Hyperactivity (present) , Intellectual disability, severe (present) (less)
Sex: male
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Pathogenic
(Jun 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004294050.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg224 amino acid residue in DEAF1. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg224 amino acid residue in DEAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24726472, 32959227, 33705764). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects DEAF1 function (PMID: 24726472). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DEAF1 protein function. ClinVar contains an entry for this variant (Variation ID: 133293). This missense change has been observed in individual(s) with autosomal dominant DEAF1-related conditions (PMID: 33705764). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the DEAF1 protein (p.Arg224Trp). (less)
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Pathogenic
(Feb 01, 2024)
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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: SCV001500441.23
First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024 |
Comment:
DEAF1: PS2:Very Strong, PM1, PM2, PS3:Supporting
Number of individuals with the variant: 2
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Pathogenic
(May 01, 2014)
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no assertion criteria provided
Method: literature only
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VULTO-VAN SILFHOUT-DE VRIES SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000154731.3
First in ClinVar: Jun 09, 2014 Last updated: Jun 07, 2020 |
Comment on evidence:
In a 10-year-old boy with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Vulto-van Silfhout et al. (2014) identified a de novo heterozygous c.670C-T transition (c.670C-T, NM_021008.2) … (more)
In a 10-year-old boy with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Vulto-van Silfhout et al. (2014) identified a de novo heterozygous c.670C-T transition (c.670C-T, NM_021008.2) in the DEAF1 gene, resulting in an arg224-to-trp (R224W) substitution at a highly conserved residue in the SAND domain, which is essential for DNA binding. The mutation was not present in the dbSNP (build 139) or Exome Variant Server databases, or in over 2,000 in-house control exomes. In vitro functional expression studies demonstrated that the R224W mutation resulted in loss of the ability to repress the DEAF1 promoter, loss of DNA binding, loss of transcriptional activation of a reporter construct, and decreased interaction with XRCC6 (152690). The patient also carried a heterozygous c.1570C-T transition in the SCN2A gene (182390), resulting in an arg524-to-ter (R524X) substitution, which may have influenced the severity of the intellectual disability; however, the patient did not have a history of epilepsy. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929326.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956918.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
Comment:
Comment:
Criteria applied: PS2_MOD,PS4_MOD,PS3_SUP,PM2_SUP, PP3; 5x path in ClinVar but 6x in gnomad4.0
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg224 amino acid residue in DEAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24726472, 32959227, 33705764). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects DEAF1 function (PMID: 24726472). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DEAF1 protein function. ClinVar contains an entry for this variant (Variation ID: 133293). This missense change has been observed in individual(s) with autosomal dominant DEAF1-related conditions (PMID: 33705764). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the DEAF1 protein (p.Arg224Trp).
Comment:
DEAF1: PS2:Very Strong, PM1, PM2, PS3:Supporting
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:
Published functional studies demonstrate a damaging effect on transcriptional regulation (Vulto-van Silfhout et al., 2014); 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: 28940898, 24726472, 33705764)
Comment:
Criteria applied: PS2_MOD,PS4_MOD,PS3_SUP,PM2_SUP, PP3; 5x path in ClinVar but 6x in gnomad4.0
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg224 amino acid residue in DEAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24726472, 32959227, 33705764). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects DEAF1 function (PMID: 24726472). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DEAF1 protein function. ClinVar contains an entry for this variant (Variation ID: 133293). This missense change has been observed in individual(s) with autosomal dominant DEAF1-related conditions (PMID: 33705764). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the DEAF1 protein (p.Arg224Trp).
Comment:
DEAF1: PS2:Very Strong, PM1, PM2, PS3:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| De novo variants of DEAF1 cause intellectual disability in six Chinese patients. | Chen S | Clinica chimica acta; international journal of clinical chemistry | 2021 | PMID: 33705764 |
| Clinical Utility of Next-Generation Sequencing for Developmental Disorders in the Rehabilitation Department: Experiences from a Single Chinese Center. | Liu Y | Journal of molecular neuroscience : MN | 2021 | PMID: 32959227 |
| Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems. | Vulto-van Silfhout AT | American journal of human genetics | 2014 | PMID: 24726472 |
Text-mined citations for rs587777408 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.