NM_021008.4(DEAF1):c.670C>T (p.Arg224Trp) AND Intellectual disability, autosomal dominant 24

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 3, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000119806.6

Allele description

NM_021008.4(DEAF1):c.670C>T (p.Arg224Trp)

Gene:

DEAF1:DEAF1 transcription factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_021008.4(DEAF1):c.670C>T (p.Arg224Trp)

HGVS:

NC_000011.10:g.686992G>A
NG_034156.2:g.25092C>T
NM_001293634.1:c.664+919C>T
NM_001367390.1:c.-57C>T
NM_021008.4:c.670C>TMANE SELECT
NP_066288.2:p.Arg224Trp
NC_000011.9:g.686992G>A
NM_021008.2:c.670C>T
O75398:p.Arg224Trp

Protein change:

R224W; ARG224TRP

Links:

UniProtKB: O75398#VAR_071371; OMIM: 602635.0003; dbSNP: rs587777408

NCBI 1000 Genomes Browser:

rs587777408

Molecular consequence:

NM_001367390.1:c.-57C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293634.1:c.664+919C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_021008.4:c.670C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Intellectual disability, autosomal dominant 24 (VSVS)
Synonyms:: VULTO-VAN SILFHOUT-DE VRIES SYNDROME
Identifiers:: MONDO: MONDO:0014357; MedGen: C4014414; OMIM: 615828

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000154731	OMIM	no assertion criteria provided	Pathogenic (May 1, 2014)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004242386	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 3, 2023)	unknown	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

SCV000154731

OMIM

no assertion criteria provided

Pathogenic
(May 1, 2014)

germline

literature only

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

SCV004242386

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 3, 2023)

unknown

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems.

Vulto-van Silfhout AT, Rajamanickam S, Jensik PJ, Vergult S, de Rocker N, Newhall KJ, Raghavan R, Reardon SN, Jarrett K, McIntyre T, Bulinski J, Ownby SL, Huggenvik JI, McKnight GS, Rose GM, Cai X, Willaert A, Zweier C, Endele S, de Ligt J, van Bon BW, Lugtenberg D, et al.

Am J Hum Genet. 2014 May 1;94(5):649-61. doi: 10.1016/j.ajhg.2014.03.013. Epub 2014 Apr 10.

PubMed [citation]

PMID:: 24726472
PMCID:: PMC4067565

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000154731.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004242386.1

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

Description

Criteria applied: PS2_MOD,PS4_MOD,PS3_SUP,PM2_SUP, PP3; 5x path in ClinVar but 6x in gnomad4.0

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

Last Updated: Mar 22, 2025

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