Submissions for variant NM_139058.3(ARX):c.91A>C (p.Ser31Arg)

gnomAD frequency: 0.00002  dbSNP: rs878853107

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224602	SCV000281581	uncertain significance	not provided	2016-05-10	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
GeneDx	RCV000224602	SCV000573656	uncertain significance	not provided	2017-03-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ARX gene. The S31R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S31R variant is observed in 2/46,995 alleles from individuals undergoing testing at GeneDx including a hemizygous individual (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S31R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000819987	SCV000960679	uncertain significance	Developmental and epileptic encephalopathy, 1; Intellectual disability, X-linked, with or without seizures, arx-related	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 31 of the ARX protein (p.Ser31Arg). 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. ClinVar contains an entry for this variant (Variation ID: 235754). 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 ARX protein function. 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.
Ambry Genetics	RCV002516241	SCV003529939	uncertain significance	Inborn genetic diseases	2022-04-21	criteria provided, single submitter	clinical testing	The c.91A>C (p.S31R) alteration is located in exon 1 (coding exon 1) of the ARX gene. This alteration results from a A to C substitution at nucleotide position 91, causing the serine (S) at amino acid position 31 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.