Submissions for variant NM_000489.6(ATRX):c.109C>T (p.Arg37Ter)

dbSNP: rs122445108

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Diagnostic Laboratory, Strasbourg University Hospital	RCV000224314	SCV000281747	pathogenic	Intellectual disability	2014-07-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000680146	SCV000807591	pathogenic	Intellectual disability-hypotonic facies syndrome, X-linked, 1	2017-09-01	criteria provided, single submitter	clinical testing	This mutation has been previously reported as disease-causing and was found once in our laboratory in an 8-year-old male with intellectual disability, hypotonia, dysmorphic features, GERD, febrile seizure, short stature, mirocephaly.
Raymond Lab, University of Cambridge	RCV000224314	SCV000897756	likely pathogenic	Intellectual disability	2019-02-13	criteria provided, single submitter	research
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000148028	SCV000965785	pathogenic	Alpha thalassemia-X-linked intellectual disability syndrome	2014-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000148028	SCV001582830	pathogenic	Alpha thalassemia-X-linked intellectual disability syndrome	2023-06-23	criteria provided, single submitter	clinical testing	Studies have shown that this premature translational stop signal does not significantly alter or has an unclear effect on ATRX gene expression (PMID: 15508018, 15591283). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11742). This premature translational stop signal has been observed in individuals with clinical features of alpha-thalassemia X-linked intellectual disability syndrome (PMID: 10632111, 15508018, 24805811). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg37*) in the ATRX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATRX are known to be pathogenic (PMID: 15591283, 18409179, 23681356).
3billion	RCV000680146	SCV002012304	pathogenic	Intellectual disability-hypotonic facies syndrome, X-linked, 1	2021-10-02	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011742.7). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000680146	SCV002512243	pathogenic	Intellectual disability-hypotonic facies syndrome, X-linked, 1	2021-06-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PP1 very strong
Ambry Genetics	RCV002444427	SCV002733914	pathogenic	Inborn genetic diseases	2019-12-27	criteria provided, single submitter	clinical testing	The p.R37* pathogenic mutation (also known as c.109C>T), located in coding exon 2 of the ATRX gene, results from a C to T substitution at nucleotide position 109. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been shown to segregate with disease in several large families with variable intellectual disability (mild to profound), speech impairment, facial anomalies including +/- hypertelorism, short philtrum, open mouth, full lower lip, and microcephaly, growth deficiency, hypotonia, +/- seizures, +/- urogenital anomalies, and decreased Hgb H inclusions compared to most ATRX probands (Basehore MJ et al. Clin. Genet., 2015 May;87:461-6, Guerrini, R et al. Ann. Neurol. 2000;47(1):117-21, Moncini, S et al. Meta Gene 2013;1:102-108). This mutation is often observed to result in a less severe phenotype than is typically observed in patients with nonsense mutations in the ATRX gene, (Abidi, FE et al. Eur. J. Hum. Genet. 2005;13(2):176-83, Howard, MT et al. Med. Genet. 2004;41(12):951-6). Unaffected female carriers for this mutation have been observed to have highly skewed X-inactivation patterns of >90:10 (Abidi, FE et al. Eur. J. Hum. Genet. 2005;13(2):176-83, Basehore MJ et al. Clin. Genet., 2015 May;87:461-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000148028	SCV002769265	pathogenic	Alpha thalassemia-X-linked intellectual disability syndrome	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with both X-linked dominant and recessive disease (OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 35). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other NMD-predicted variants have previously been reported as pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in more than 20 male patients with intellectual disability (ClinVar, PMID: 26350204, PMID: 24805811). (P) 0901 - Strong evidence for segregation with disease. The variant has been shown to segregate with disease in affected males in at least 5 families, with unaffected female carriers (PMID: 24805811). (P) 1102 - Strong phenotype match. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
GeneDx	RCV003151722	SCV003840738	pathogenic	not provided	2022-09-12	criteria provided, single submitter	clinical testing	Segregates with X-linked intellectual disability, short stature, microcephaly, and dysmorphic features in multiple families; the heterozygous unaffected females showed skewed X-inactivation (Abidi et al., 2005; Basehore et al., 2015); Functional studies suggest that the variant may cause reduced protein expression compared to WT, however additional studies are needed to validate the impact of this variant on splicing (Howard et al., 2004); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32170002, 3239563, 25606380, 18409179, 25167861, 25326635, 20301622, 28293299, 33173999, 25679214, 26147798, 31685013, 29491882, 26997013, 20865721, 32277047, 26350204, 30231518, 36031702, 12953102, 28152038, 31452935, 24805811, 10632111, 15508018, 32901917, 15591283)
OMIM	RCV000012508	SCV000032742	pathogenic	Intellectual disability-hypotonic facies syndrome, X-linked	2004-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000148028	SCV000195529	not provided	Alpha thalassemia-X-linked intellectual disability syndrome		no assertion provided	literature only