VCV002336360.4 - ClinVar

NM_021008.4(DEAF1):c.723G>C (p.Glu241Asp)

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.

(2)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_021008.4(DEAF1):c.723G>C (p.Glu241Asp)

Variation ID: 2336360 Accession: VCV002336360.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 686939 (GRCh38) [ NCBI UCSC ] 11: 686939 (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	Feb 8, 2023	Oct 26, 2024	Oct 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_021008.4:c.723G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066288.2:p.Glu241Asp	missense
NM_001293634.1:c.664+972G>C		intron variant
NM_001367390.1:c.-4G>C		5 prime UTR
NC_000011.10:g.686939C>G
NC_000011.9:g.686939C>G
NG_034156.2:g.25145G>C
NG_121486.1:g.454C>G

... more HGVS ... less HGVS

Protein change

E241D

Other names

Canonical SPDI

NC_000011.10:686938:C:G

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

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.
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.
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jan 31, 2023	RCV002930861.3
not provided	Uncertain significance (1)	criteria provided, single submitter	Oct 10, 2023	RCV004765725.1

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.
Uncertain significance (Jan 31, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003666890.3 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 9697411‚ 24726472‚ 33726816 Comment: The c.723G>C (p.E241D) alteration is located in exon 5 (coding exon 5) of the DEAF1 gene. This alteration results from a G to C substitution … (more) The c.723G>C (p.E241D) alteration is located in exon 5 (coding exon 5) of the DEAF1 gene. This alteration results from a G to C substitution at nucleotide position 723, causing the glutamic acid (E) at amino acid position 241 to be replaced by an aspartic acid (D). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Another alteration at the same codon, c.721G>A (p.E241K), has been reported as de novo in one individual; however, clinical details were not provided (Stranneheim, 2021). This amino acid position is well conserved in available vertebrate species. Based on internal structural analysis, E241D is near the KDWK motif critical to DNA-binding, but its potential impact on the motif is unclear (Gibson, 1998; Vulto-van Silfhout, 2014). This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Oct 10, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005380095.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	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; Has not been previously published as pathogenic or benign to our knowledge (less)

Comment:

The c.723G>C (p.E241D) alteration is located in exon 5 (coding exon 5) of the DEAF1 gene. This alteration results from a G to C substitution at nucleotide position 723, causing the glutamic acid (E) at amino acid position 241 to be replaced by an aspartic acid (D). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Another alteration at the same codon, c.721G>A (p.E241K), has been reported as de novo in one individual; however, clinical details were not provided (Stranneheim, 2021). This amino acid position is well conserved in available vertebrate species. Based on internal structural analysis, E241D is near the KDWK motif critical to DNA-binding, but its potential impact on the motif is unclear (Gibson, 1998; Vulto-van Silfhout, 2014). This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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; Has not been previously published as pathogenic or benign to our knowledge

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
Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.	Stranneheim H	Genome medicine	2021	PMID: 33726816
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
The APECED polyglandular autoimmune syndrome protein, AIRE-1, contains the SAND domain and is probably a transcription factor.	Gibson TJ	Trends in biochemical sciences	1998	PMID: 9697411

Text-mined citations for this variant ...

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_021008.4(DEAF1):c.723G>C (p.Glu241Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...