ClinVar Miner

Submissions for variant NM_000489.5(ATRX):c.736C>T (p.Arg246Cys) (rs122445105)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078972 SCV000110837 pathogenic not provided 2014-01-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000190796 SCV000244237 pathogenic Inborn genetic diseases 2013-09-03 criteria provided, single submitter clinical testing
GeneDx RCV000078972 SCV000329092 pathogenic not provided 2017-09-07 criteria provided, single submitter clinical testing The R246C variant in the ATRX gene (previously published as R129C due to alternative nomenclature) is a recurrent variant that has been identified in multiple unrelated patients with alpha-thalassemia X-linked intellectual disability (Gibbons et al., 1997; Gibbons et al., 2008; Pavone et al., 2010). The R246C mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R246C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R246C as a disease-causing variant
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659281 SCV000781081 pathogenic Alpha thalassemia-X-linked intellectual disability syndrome 2016-11-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763634 SCV000894504 pathogenic Acquired hemoglobin H disease; Alpha thalassemia-X-linked intellectual disability syndrome; Mental retardation-hypotonic facies syndrome X-linked, 1 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000659281 SCV001201707 pathogenic Alpha thalassemia-X-linked intellectual disability syndrome 2019-08-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 246 of the ATRX protein (p.Arg246Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with alpha-thalassemia X-linked intellectual disability syndrome, and has been shown to segregate with disease in several families (PMID: 9326931, 16955409, 20500465, 24327140). This variant is also known as p.Arg129Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 11735). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078972 SCV001248379 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV001249275 SCV001423220 not provided Renier-Gabreels-Jasper syndrome no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 01-31-2016 by Lab or GTR ID 506634. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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