Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002449713 | SCV002682197 | likely pathogenic | Inborn genetic diseases | 2018-03-07 | criteria provided, single submitter | clinical testing | The p.R290H variant (also known as c.869G>A), located in coding exon 6 of the ARHGEF9 gene, results from a G to A substitution at nucleotide position 869. The arginine at codon 290 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in a male with seizures and intellectual disability (Lemke JR et al. Epilepsia, 2012 Aug;53:1387-98). This variant was shown to impair proper function of the ARHGEF9 protein (Papadopoulos T et al. J. Biol. Chem., 2015 Mar;290:8256-70; Long P et al. Front Mol Neurosci, 2015 Jan;8:83). Internal structural analysis indicates that this alteration is structurally deleterious (Ambry internal data; Xiang S et al. J. Mol. Biol., 2006 May;359:35-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Division Of Personalized Genomic Medicine, |
RCV002512195 | SCV002822963 | likely pathogenic | Developmental and epileptic encephalopathy, 8 | 2019-07-24 | criteria provided, single submitter | clinical testing | The c.890G>A variant in the ARHGEF9 gene is a hemizygous missense variant, which results in the substitution of the highly conserved arginine residue at position 297 to histidine (p.Arg297His). It is predicted to be deleterious and damaging to protein structure and/or function by PROVEAN and SIFT, respectively.This variant has not been observed in the Genome Aggregation Database (gnomAD), indicating it is not a common benign variant in the populations represented in this database. This exact variant has been previously reported in one adult male patient with generalized tonic-clonic seizures and mental retardation (PMID: 22612257, case B310). Although the patient had two adult brothers with a similar phenotype, segregation analysis was not performed to determine whether they carried the same variant. In addition, a different amino acid change at the same position (p.Arg290Cys) has been reported in four male siblings with epileptic encephalopathy and intellectual disability (PMID: 29130122). In functional studies, the p.Arg297His variant was found to affect inhibitory synapse formation by altering the strength intramolecular interactions between the diffuse B-cell lymphoma homology domain (DH) and the pleckstrin homology domain (PH) of collybistin, the enzyme encoded by ARHGEF9. This defect reduced the phosphatidylinositol 3-phosphate (PIP3P) binding affinity of collybistin, limiting its normal synaptogenic activity (PMID: 25678704). Given this evidence, this variant is classified as a likely pathogenic variant. |
| Labcorp Genetics |
RCV002512195 | SCV003445159 | pathogenic | Developmental and epileptic encephalopathy, 8 | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 290 of the ARHGEF9 protein (p.Arg290His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ARHGEF9-related conditions (PMID: 22612257, 28589176). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1764342). 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 ARHGEF9 protein function. Experimental studies have shown that this missense change affects ARHGEF9 function (PMID: 25678704, 30914922). This variant disrupts the p.Arg290 amino acid residue in ARHGEF9. Other variant(s) that disrupt this residue have been observed in individuals with ARHGEF9-related conditions (PMID: 29130122), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |