Submissions for variant NM_000489.6(ATRX):c.736C>T (p.Arg246Cys)

dbSNP: rs122445105

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	2022-05-19	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 (gnomAD); 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: 16955409, 27899421, 25590979, 9326931, 20500465, 24327140, 21666679, 21421568, 31130284, 32369273, 34051360, 17609377, 18409179)
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; Intellectual disability-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	2023-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 246 of the ATRX protein (p.Arg246Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alpha-thalassemia X-linked intellectual disability syndrome (PMID: 9326931, 16955409, 20500465, 24327140). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg129Cys. ClinVar contains an entry for this variant (Variation ID: 11735). 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 ATRX protein function. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics 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
3billion	RCV001252427	SCV002058254	pathogenic	Intellectual disability-hypotonic facies syndrome, X-linked, 1	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16955409, 20500465, 31130284, PS4_S). The variant was co-segregated with Mental retardation-hypotonic facies syndrome, X-linked in multiple affected family members (PMID: 20500465, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.972, 3CNET: 0.905, PP3_P). A missense variant is a common mechanism associated with Mental retardation-hypotonic facies syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). A different missense change at the same codon has been reported to be associated with ATRX related disorder (PMID:10660327, PM5_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000659281	SCV004123046	pathogenic	Alpha thalassemia-X-linked intellectual disability syndrome	2023-07-01	criteria provided, single submitter	research
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	Intellectual disability-hypotonic facies syndrome, X-linked, 1	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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078972	SCV001951936	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078972	SCV001968052	pathogenic	not provided		no assertion criteria provided	clinical testing