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

dbSNP: rs587777408

Total submissions: 7

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001310582	SCV004294050	pathogenic	not provided	2023-06-05	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 133293). 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. Experimental studies have shown that this missense change affects DEAF1 function (PMID: 24726472). 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. For these reasons, this variant has been classified as Pathogenic.
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