ClinVar Miner

Submissions for variant NM_015185.3(ARHGEF9):c.865C>T (p.Arg289Ter) (rs1135401795)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000627195 SCV000748179 pathogenic not provided 2018-02-13 criteria provided, single submitter clinical testing The R289X nonsense variant in the ARHGEF9 gene was previously identified as a de novo variant with confirmed parentage in a patient with a neurodevelopmental disorder who was tested at GeneDx (Retterer et al., 2016), and it was identified in the hemizygous state in an unrelated patient with epilepsy. It has also been reported previously in the heterozygous state in a female with intellectual disability and macrocephaly whose father was mosaic for the variant, although no clinical information was provided about her father (Chérot et al., 2017). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R289X variant is not observed in large population cohorts (Lek et al., 2016). Therefore, the R289X is interpreted as a pathogenic variant.
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement,Assistance Publique Hopitaux de Paris RCV000496205 SCV000586750 pathogenic Early infantile epileptic encephalopathy 8 2017-01-06 criteria provided, single submitter clinical testing Intellectual Disability; relative macrocephaly
Invitae RCV000496205 SCV000823964 pathogenic Early infantile epileptic encephalopathy 8 2018-02-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg289*) in the ARHGEF9 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with early infantile epileptic encephalopathy (PMID: 28708303). ClinVar contains an entry for this variant (Variation ID: 431121). Loss-of-function variants in ARHGEF9 are known to be pathogenic (PMID: 23033978, 25678704, 26834553). For these reasons, this variant has been classified as Pathogenic.

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