Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001194458 | SCV001364043 | likely pathogenic | Intellectual disability, X-linked, with or without seizures, arx-related | 2019-04-30 | criteria provided, single submitter | clinical testing | Variant summary: ARX c.1187dupC (p.Gly397TrpfsX135) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in patients affected with severe forms of ARX-Related Disorders (Friocourt 2010 and HGMD). The variant was absent in 89997 control chromosomes (gnomAD). c.1187dupC has been reported in the literature in a male proband affected with a severe ARX-Related Disorder, i.e. X-linked lissencephaly with abnormal genitalia (XLAG) (Kitamura 2002). Although several reports of affected females, heterozygous for severe mutations in ARX have been published, the mother of the reported proband, who also carried the variant of interest, showed no brain developmental abnormalities or seizures (Marsh 2009); authors suggested that this could be explained by skewed X chromosome inactivation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Invitae | RCV001389322 | SCV001590645 | pathogenic | Developmental and epileptic encephalopathy, 1; Intellectual disability, X-linked, with or without seizures, arx-related | 2020-09-11 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the ARX gene (p.Gly397Trpfs*135). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 166 amino acids of the ARX protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with X-linked lissencephaly with ambiguous genitalia (PMID: 12379852). ClinVar contains an entry for this variant (Variation ID: 11194). This variant disrupts the C-terminus of the ARX protein. Other variant(s) that disrupt this region (p.Arg527*) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000011945 | SCV000032179 | pathogenic | X-linked lissencephaly with abnormal genitalia | 2002-11-01 | no assertion criteria provided | literature only |