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NM_021008.4(DEAF1):c.676C>T (p.Arg226Trp) AND Intellectual disability-epilepsy-extrapyramidal syndrome

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
May 4, 2017
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:
RCV000515525.3

Allele description [Variation Report for NM_021008.4(DEAF1):c.676C>T (p.Arg226Trp)]

NM_021008.4(DEAF1):c.676C>T (p.Arg226Trp)

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.676C>T (p.Arg226Trp)
HGVS:
  • NC_000011.10:g.686986G>A
  • NG_034156.2:g.25098C>T
  • NM_001293634.1:c.664+925C>T
  • NM_001367390.1:c.-51C>T
  • NM_021008.4:c.676C>TMANE SELECT
  • NP_066288.2:p.Arg226Trp
  • NP_066288.2:p.Arg226Trp
  • NC_000011.9:g.686986G>A
  • NM_021008.2:c.676C>T
  • NM_021008.3:c.676C>T
  • O75398:p.Arg226Trp
Protein change:
R226W; ARG226TRP
Links:
UniProtKB: O75398#VAR_071372; OMIM: 602635.0005; dbSNP: rs587777623
NCBI 1000 Genomes Browser:
rs587777623
Molecular consequence:
  • NM_001367390.1:c.-51C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001293634.1:c.664+925C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_021008.4:c.676C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Intellectual disability-epilepsy-extrapyramidal syndrome (NEDHELS)
Synonyms:
Dyskinesia, seizures, and intellectual developmental disorder
Identifiers:
MONDO: MONDO:0014952; MedGen: C4310683; OMIM: 617171

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000188578OMIM
no assertion criteria provided
Pathogenic
(Jun 1, 2014)
germlineliterature only

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

SCV000590954Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(May 4, 2017)
inheritedclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
Middle Easterninheritedyes11not providednot providedyesclinical testing

Citations

PubMed

Novel homozygous DEAF1 variant suspected in causing white matter disease, intellectual disability, and microcephaly.

Faqeih EA, Al-Owain M, Colak D, Kenana R, Al-Yafee Y, Al-Dosary M, Al-Saman A, Albalawi F, Al-Sarar D, Domiaty D, Daghestani M, Kaya N.

Am J Med Genet A. 2014 Jun;164A(6):1565-70. doi: 10.1002/ajmg.a.36482. Epub 2014 Mar 25.

PubMed [citation]
PMID:
24668509

Identification of a syndrome comprising microcephaly and intellectual disability but not white matter disease associated with a homozygous c.676C>T p.R226W DEAF1 mutation.

Gund C, Powis Z, Alcaraz W, Desai S, Baranano K.

Am J Med Genet A. 2016 May;170A(5):1330-2. doi: 10.1002/ajmg.a.37580. Epub 2016 Feb 2.

PubMed [citation]
PMID:
26834045
See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000188578.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

In 2 boys from different branches of a consanguineous Saudi family with neurodevelopmental disorder with hypotonia and impaired expressive language, with or without seizures (NEDHELS; 617171), Faqeih et al. (2014) identified a homozygous c.676C-T transition (c.676C-T, NM_021008) in the DEAF1 gene, resulting in an arg226-to-trp (R226W) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing combined with homozygosity mapping, segregated with the disorder in the family. All 4 unaffected parents were heterozygous for the mutation, which was not present in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases or in 650 ethnically matched controls. One of the patients had a sister who died of a similar disorder. Functional studies of the variant were not performed. The authors noted that the R226W variant is located between previously identified heterozygous de novo mutations (602635.0002 and 602635.0003) and does not seem to interfere directly with the DNA binding domain.

In a 14-year-old boy, born of consanguineous Pakistani parents, with NEDHELS, Gund et al. (2016) identified homozygosity for the R226W mutation in the DEAF1 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in each unaffected parent. Functional studies of the variant and studies of patient cells were not performed.

In a 2-year-old boy (patient 615391) with NEDHELS, Chen et al. (2017) identified homozygosity for the c.676C-T transition in exon 5 of the DEAF1 gene, resulting in an R226W substitution at a conserved residue in the SAND domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. In vitro functional expression studies showed that the mutation had no effect on DEAF1 transcriptional repressive activity or DNA binding compared to wildtype. The mutant protein localized normally to the nucleus in cells transfected with the mutation. The variant was found at a low frequency (8.28 x 10(-6)) in the heterozygous state in the ExAC database.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV000590954.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Middle Eastern1not providedyesclinical testing
(GTR000508680.4)
PubMed (5)

Description

This missense variant has been reported in 2 unrelated families and observed once in our laboratory homozygous in a 2-year-old male with developmental delay, hypotonia, microcephaly, failure to thrive, and a family history of a similar disorder. This individual was included in one of the reports (PMID: 24668509).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot provided
(GTR000508680.4)
1not provided1not provided

Last Updated: Feb 20, 2024