ClinVar Miner

Submissions for variant NM_139058.3(ARX):c.997A>G (p.Thr333Ala)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV005220265 SCV005860467 uncertain significance Developmental and epileptic encephalopathy, 1; Intellectual disability, X-linked, with or without seizures, arx-related 2024-07-09 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 333 of the ARX protein (p.Thr333Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ARX-related conditions. 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) performed at Invitae indicates that this missense variant is expected to disrupt ARX protein function with a positive predictive value of 80%. This variant disrupts the p.Thr333 amino acid residue in ARX. Other variant(s) that disrupt this residue have been observed in individuals with ARX-related conditions (PMID: 14722918, 23583054), which suggests that this may be a clinically significant amino acid residue. 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.

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