ClinVar Miner

Submissions for variant NM_000489.5(ATRX):c.2875G>T (p.Asp959Tyr) (rs1057523431)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000417534 SCV000531986 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing The D959Y variant in the ATRX gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D959Y variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D959Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D959Y as a variant of uncertain significance.
Invitae RCV000809360 SCV000949510 uncertain significance ATR-X syndrome 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 959 of the ATRX protein (p.Asp959Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATRX-related disease. ClinVar contains an entry for this variant (Variation ID: 389447). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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