Submissions for variant NM_014423.4(AFF4):c.772C>T (p.Arg258Trp)

dbSNP: rs786205680

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485909	SCV000567321	pathogenic	not provided	2018-09-26	criteria provided, single submitter	clinical testing	The R258W variant in the AFF4 gene has been reported previously as a de novo sequence change in anindividual with CHOPS syndrome who presented with cognitive impairment, coarse features, heart defects,obesity, pulmonary involvement and short stature (Izumi et al., 2015). Functional studies supportedpathogenicity in that R258W results in a significantly reduced proteosomal degradation in anoverexpression model using HEK-293T cells, whereas transcriptional targets MYC gene and JUN genewere upregulated in the variant compared to wild type in this overexpression model. In addition, patient-derived fibroblasts had significantly elevated AFF4 protein levels, and upregulation of MYC expression, butnot that of JUN (Izumi et al., 2015). Furthermore, missense variants in nearby residues (T254A, T254S)have been reported in the Human Gene Mutation Database in association with CHOPS syndrome(Stenson et al., 2014), supporting the functional importance of this region of the protein. The R258Wsubstitution was not observed in approximately 6500 individuals of European and African American ancestryin the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The R258W variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties. This substitutionoccurs at a position that is conserved across species. In silico analysis predicts this variant is probablydamaging to the protein structure/function. We interpret R258W as a pathogenic variant.
Invitae	RCV000170517	SCV000822659	pathogenic	Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	2017-06-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change leads to increased AFF4 protein levels and higher expression of transcriptional target genes (PMID: 25730767). This variant has been reported to be de novo in an individual affected with CHOPS syndrome (PMID: 25730767). ClinVar contains an entry for this variant (Variation ID: 190331). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 258 of the AFF4 protein (p.Arg258Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000170517	SCV000966177	likely pathogenic	Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	2018-08-07	criteria provided, single submitter	clinical testing
OMIM	RCV000170517	SCV000222949	pathogenic	Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	2015-04-01	no assertion criteria provided	literature only