Submissions for variant NM_000489.6(ATRX):c.2066A>G (p.Gln689Arg)

gnomAD frequency: 0.00001  dbSNP: rs929951326

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520365	SCV000618959	uncertain significance	not provided	2017-07-13	criteria provided, single submitter	clinical testing	The Q689R variant in the ATRX gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Q689R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Q689R 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 not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret Q689R as a variant of uncertain significance.
Ambry Genetics	RCV002314911	SCV000847940	uncertain significance	Inborn genetic diseases	2016-10-04	criteria provided, single submitter	clinical testing	The p.Q689R variant (also known as c.2066A>G), located in coding exon 9 of the ATRX gene, results from an A to G substitution at nucleotide position 2066. The glutamine at codon 689 is replaced by arginine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002497020	SCV002815251	uncertain significance	Acquired hemoglobin H disease; Alpha thalassemia-X-linked intellectual disability syndrome; Intellectual disability-hypotonic facies syndrome, X-linked, 1	2022-04-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001271463	SCV002990542	uncertain significance	Alpha thalassemia-X-linked intellectual disability syndrome	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 689 of the ATRX protein (p.Gln689Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATRX-related conditions. ClinVar contains an entry for this variant (Variation ID: 450381). 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 not expected to disrupt ATRX 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003139735	SCV003807727	uncertain significance	Intellectual disability-hypotonic facies syndrome, X-linked, 1	2021-12-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, BP4 supporting
Natera, Inc.	RCV001271463	SCV001452624	uncertain significance	Alpha thalassemia-X-linked intellectual disability syndrome	2020-09-16	no assertion criteria provided	clinical testing