Submissions for variant NM_000489.6(ATRX):c.5579A>G (p.Asn1860Ser)

gnomAD frequency: 0.00663  dbSNP: rs45439799

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078966	SCV000110831	benign	not specified	2013-11-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000078966	SCV000150400	benign	not specified	2014-01-24	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000428077	SCV000510722	benign	not provided	2016-06-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012490	SCV000639896	benign	Alpha thalassemia-X-linked intellectual disability syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311512	SCV000845878	benign	Inborn genetic diseases	2016-01-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000012490	SCV000883115	likely benign	Alpha thalassemia-X-linked intellectual disability syndrome	2018-11-21	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000428077	SCV001143149	benign	not provided	2018-12-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012490	SCV001440402	benign	Alpha thalassemia-X-linked intellectual disability syndrome	2019-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000012490	SCV001737233	benign	Alpha thalassemia-X-linked intellectual disability syndrome	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000428077	SCV001874010	benign	not provided	2018-09-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31019283, 28293299, 28492530, 8968741, 29602769, 18805826, 29304373, 24728327, 22995991, 24082139, 7697714)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000078966	SCV002103505	benign	not specified	2022-02-18	criteria provided, single submitter	clinical testing	Variant summary: ATRX c.5579A>G (p.Asn1860Ser) results in a conservative amino acid change located in the SNF2, N-terminal domain (IPR000330) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 183291 control chromosomes, predominantly at a frequency of 0.01 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATRX causing ATR-X Syndrome phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign (n=8) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004593961	SCV005086712	benign	Intellectual disability-hypotonic facies syndrome, X-linked, 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of intellectual disability-hypotonic facies syndrome, X-linked (MIM#309580), with 539 hemizygotes and 2 homozygotes in gnomAD v2. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Breakthrough Genomics, Breakthrough Genomics	RCV000428077	SCV005210647	likely benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000012490	SCV000032724	pathogenic	Alpha thalassemia-X-linked intellectual disability syndrome	1995-03-24	no assertion criteria provided	literature only
ITMI	RCV000078966	SCV000084318	not provided	not specified	2013-09-19	no assertion provided	reference population
Tampere Brain Tumor Research Consortium, University of Tampere	RCV000588578	SCV000693709	pathogenic	Atypical teratoid rhabdoid tumor		no assertion criteria provided	research
Tampere Brain Tumor Research Consortium, University of Tampere	RCV000590248	SCV000693710	pathogenic	Astrocytoma, anaplastic		no assertion criteria provided	research
Natera, Inc.	RCV000012490	SCV001462649	benign	Alpha thalassemia-X-linked intellectual disability syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000078966	SCV001548771	benign	not specified		no assertion criteria provided	clinical testing	The ATRX p.Asn1822Ser variant was identified in the literature as a heterozygous variant in a mother and daughter with familial brain tumors; both patients also carried a TP53 variant known to cause Li Fraumeni syndrome (Nordfors_2018_PMID:29602769). The variant was also identified in 1 family with ATR-X syndrome, however the variant was suggested to have uncertain significance (Gibbons_1995_PMID:7697714). The variant was identified in dbSNP (ID: rs45439799) and ClinVar (classified as benign by Invitae, Ambry Genetics and three other clinical laboratories, classified as likely benign by Equipe Genetique des Anomalies du Developpement Université de Bourgogne, and classified as pathogenic by Tampere Brain Tumor Research Consortium University of Tampere). The variant was identified in control databases in 1371 of 205163 chromosomes (2 homozygous; 539 hemizygous) at a frequency of 0.006682 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 196 of 18551 chromosomes (freq: 0.01057), African in 947 of 92618 chromosomes (freq: 0.01022), Latino in 77 of 7663 chromosomes (freq: 0.01005), Ashkenazi Jewish in 37 of 5322 chromosomes (freq: 0.006952), South Asian in 57 of 19074 chromosomes (freq: 0.002988), European (Finnish) in 35 of 28028 chromosomes (freq: 0.001249) and Other in 22 of 19044 chromosomes (freq: 0.001155), but was not observed in the East Asian population. The p.Asn1822 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000428077	SCV001742261	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000428077	SCV001798950	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000428077	SCV001931329	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078966	SCV001954977	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078966	SCV001975898	benign	not specified		no assertion criteria provided	clinical testing