Submissions for variant NM_139058.3(ARX):c.1105G>A (p.Glu369Lys)

dbSNP: rs104894746

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000442107	SCV000523951	likely pathogenic	not provided	2023-06-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20300201)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779752	SCV000916527	uncertain significance	not specified	2018-11-06	criteria provided, single submitter	clinical testing	Variant summary: ARX c.1105G>A (p.Glu369Lys) results in a conservative amino acid change located in the Homeobox domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 20124 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1105G>A in individuals affected with AXR-Related Disorder and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000990555	SCV001141566	likely pathogenic	Developmental and epileptic encephalopathy, 1	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000990555	SCV001429460	likely pathogenic	Developmental and epileptic encephalopathy, 1	2018-07-02	criteria provided, single submitter	clinical testing	This variant was identified as hemizygous
Invitae	RCV001372869	SCV001569560	uncertain significance	Developmental and epileptic encephalopathy, 1; Intellectual disability, X-linked, with or without seizures, arx-related	2022-04-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 369 of the ARX protein (p.Glu369Lys). 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: 383533). 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. 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.