Submissions for variant NM_000489.6(ATRX):c.7156C>T (p.Arg2386Ter)

dbSNP: rs122445099

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723525	SCV000331241	pathogenic	not provided	2016-04-25	criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV005055347	SCV000854495	pathogenic	HP:0000028 (present); HP:0000062 (present); HP:0000252 (present); HP:0002669 (present); HP:0010864 (present)	2018-11-19	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000723525	SCV001448164	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012494	SCV002230912	pathogenic	Alpha thalassemia-X-linked intellectual disability syndrome	2024-08-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2386*) in the ATRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 107 amino acid(s) of the ATRX protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with alpha-thalassemia X-linked intellectual disability syndrome (PMID: 7697714, 24690944, 28371217). It has also been observed to segregate with disease in related individuals. This variant is also known as C4635T (R1528*). ClinVar contains an entry for this variant (Variation ID: 11728). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics	RCV002283442	SCV002572629	pathogenic	Intellectual disability-hypotonic facies syndrome, X-linked, 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 24690944 , 28371217 , 7697714). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011728 / PMID: 7697714). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012494	SCV005400355	pathogenic	Alpha thalassemia-X-linked intellectual disability syndrome	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ATRX-related conditions. (I) 0108 - This gene is associated with both X-linked recessive and dominant disease. Carrier females may be asymptomatic, or affected with alpha-thalassaemia syndrome (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable severity and phenotypes have been observed among individuals with the same variant (PMID: 24805811, 23820649). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Four downstream truncating variants have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000012494	SCV000032728	pathogenic	Alpha thalassemia-X-linked intellectual disability syndrome	1995-03-24	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004532323	SCV004120580	pathogenic	ATRX-related disorder	2024-03-01	no assertion criteria provided	clinical testing	The ATRX c.7156C>T variant is predicted to result in premature protein termination (p.Arg2386*). This variant has been reported in multiple individuals with X-linked intellectual disability syndrome (Gibbons et al 1995. PubMed ID: 7697714; Brett M et al 2014. PubMed ID: 24690944; Ji J et al 2017. PubMed ID: 28371217). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in ATRX are expected to be pathogenic. This variant is interpreted as pathogenic.