Submissions for variant NM_021008.4(DEAF1):c.671G>A (p.Arg224Gln)

gnomAD frequency: 0.00001  dbSNP: rs1415420832

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV003127670	SCV003804018	likely pathogenic	Autism spectrum disorder		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003718379	SCV004511913	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 915957). This missense change has been observed in individual(s) with autosomal recessive DEAF1-related conditions (PMID: 30923367). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal dominant DEAF1-related conditions (PMID: 32094338); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 224 of the DEAF1 protein (p.Arg224Gln). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DEAF1 function (PMID: 30923367).
GeneDx	RCV003718379	SCV005379576	likely pathogenic	not provided	2024-04-18	criteria provided, single submitter	clinical testing	Observed in patient with severe intellectual disability and autism; however, the variant was inherited from an unaffected parent (PMID: 32094338); 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: 30923367, 32094338, 33705764, 33057194, 35982159, 24726472)
OMIM	RCV001171489	SCV001334291	pathogenic	Intellectual disability-epilepsy-extrapyramidal syndrome	2020-06-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004528401	SCV004110323	likely pathogenic	DEAF1-related disorder	2024-06-17	no assertion criteria provided	clinical testing	The DEAF1 c.671G>A variant is predicted to result in the amino acid substitution p.Arg224Gln. This variant has been reported in the homozygous state in a pair of siblings with severe intellectual disability and developmental regression (Nabais Sá et al. 2019. PubMed ID: 30923367). It has also been reported de novo in an individual with an unspecified developmental disorder (Kaplanis et al. 2020. PubMed ID: 33057194) and as a maternally inherited heterozygous variant in an individual with autism spectrum disorder (Husson et al. 2020. PubMed ID: 32094338). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Of note, two additional missense variants affecting the same amino acid residue (p.Arg224Trp, p.Arg224Gly) have been reported de novo in individuals with DEAF1-associated neurodevelopmental disorders (Vulto-van Silfhout et al. 2014. PubMed ID: 24726472; Liu et al. 2016. PubMed ID: 32959227; Chen et al. 2021. PubMed ID: 33705764). Taken together, the p.Arg224Gln variant is interpreted as likely pathogenic.