ClinVar Miner

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

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Total submissions: 14
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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 2019-05-08 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (Iwase et al., 2011; Dhayalan et al., 2011); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16955409, 27899421, 25590979, 9326931, 18409179, 20500465, 24327140, 21666679, 21421568, 31130284, 32369273)
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; X-linked intellectual disability-hypotonic face syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000659281 SCV001201707 pathogenic Alpha thalassemia-X-linked intellectual disability syndrome 2019-08-30 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000659281 SCV001442634 pathogenic Alpha thalassemia-X-linked intellectual disability syndrome 2020-10-15 criteria provided, single submitter clinical testing Variant summary: ATRX c.736C>T (p.Arg246Cys) results in a non-conservative amino acid change located in the ADD (Zinc finger) domain (IPR025766) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 181349 control chromosomes. c.736C>T has been reported in the literature in multiple individuals affected with ATR-X Syndrome (example, Gibbons_1997, Wada_2000, Badens_2006, Pavone_2010, Monies_2019, Zhu_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=5)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000078972 SCV001447677 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux RCV000078972 SCV001468949 likely pathogenic not provided 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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252427 SCV001428183 likely pathogenic X-linked intellectual disability-hypotonic face syndrome 2019-01-01 no assertion criteria provided clinical testing
Natera, Inc. RCV000659281 SCV001452631 pathogenic Alpha thalassemia-X-linked intellectual disability syndrome 2020-09-16 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000078972 SCV001951936 pathogenic not provided no assertion criteria provided clinical testing

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