ClinVar Miner

Submissions for variant NM_139058.3(ARX):c.1561G>A (p.Ala521Thr)

gnomAD frequency: 0.00002  dbSNP: rs746120093
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000193135 SCV000246554 uncertain significance not specified 2013-02-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000624792 SCV000741585 uncertain significance Inborn genetic diseases 2016-06-06 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001046771 SCV001210686 uncertain significance Developmental and epileptic encephalopathy, 1; Intellectual disability, X-linked, with or without seizures, arx-related 2022-02-09 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 521 of the ARX protein (p.Ala521Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with ARX-related conditions (PMID: 14722918; Invitae). ClinVar contains an entry for this variant (Variation ID: 210322). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000193135 SCV005380975 uncertain significance not specified 2024-08-30 criteria provided, single submitter clinical testing Variant summary: ARX c.1561G>A (p.Ala521Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 111006 control chromosomes, including one hemizygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1561G>A has been reported in the literature in an individual affected with X-linked lissencephaly with abnormal genitalia and cerebellar hypoplasia (Kato_2004). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 14722918). ClinVar contains an entry for this variant (Variation ID: 210322). Based on the evidence outlined above, the variant was classified as uncertain significance.
Diagnostic Laboratory, Strasbourg University Hospital RCV001249486 SCV001423476 uncertain significance Intellectual disability 2018-12-01 no assertion criteria provided clinical testing

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