ClinVar Miner

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

dbSNP: rs587777408
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001310582 SCV001500441 pathogenic not provided 2024-02-01 criteria provided, single submitter clinical testing DEAF1: PS2:Very Strong, PM1, PM2, PS3:Supporting
GeneDx RCV001310582 SCV002099567 pathogenic not provided 2022-01-05 criteria provided, single submitter clinical testing 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)
Institute of Human Genetics, University of Leipzig Medical Center RCV000119806 SCV004242386 likely pathogenic Intellectual disability, autosomal dominant 24 2023-12-03 criteria provided, single submitter clinical testing Criteria applied: PS2_MOD,PS4_MOD,PS3_SUP,PM2_SUP, PP3; 5x path in ClinVar but 6x in gnomad4.0
Invitae RCV001310582 SCV004294050 pathogenic not provided 2023-06-05 criteria provided, single submitter clinical testing 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).
OMIM RCV000119806 SCV000154731 pathogenic Intellectual disability, autosomal dominant 24 2014-05-01 no assertion criteria provided literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001310582 SCV001929326 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001310582 SCV001956918 pathogenic not provided no assertion criteria provided clinical testing

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