Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001879754 | SCV002138878 | uncertain significance | Developmental and epileptic encephalopathy, 8 | 2022-08-16 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the p.Arg290 amino acid residue in ARHGEF9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25678704, 28589176). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 973141). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 29130122). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 290 of the ARHGEF9 protein (p.Arg290Cys). |
| Ambry Genetics | RCV002447235 | SCV002682177 | likely pathogenic | Inborn genetic diseases | 2018-03-07 | criteria provided, single submitter | clinical testing | The p.R290C variant (also known as c.868C>T), located in coding exon 6 of the ARHGEF9 gene, results from a C to T substitution at nucleotide position 868. The arginine at codon 290 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration co-segregated with disease in one family with four male siblings who all had refractory epileptic encephalopathy and carried this alteration. The alteration was determined to be inherited from the unaffected mother (Wang JY et al. Neurogenetics, 2018 Jan;19:9-16). 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). A different alteration located at the same position, p.R290H (c.869G>A), was identified in a male with seizures and intellectual disability (Lemke JR et al. Epilepsia, 2012 Aug;53:1387-98). The p.R290H 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). 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. |
| Diagnostic Laboratory, |
RCV001249523 | SCV001423513 | uncertain significance | Autism spectrum disorder | 2017-12-01 | no assertion criteria provided | clinical testing |