ClinVar Miner

Submissions for variant NM_000489.5(ATRX):c.5722G>T (p.Asp1908Tyr) (rs1057522290)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000426830 SCV000526989 uncertain significance not provided 2016-04-15 criteria provided, single submitter clinical testing The D1908Y variant in the ATRX gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D1908Y variant was not observed in approximately 6500 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 D1908Y 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 where amino acids with similar properties to Aspartic acid are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, this variant is also predicted to create a cryptic donor site upstream of the natural donor splice site for intron 24, which could lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of D1908Y is unknown. The adjacent missense variant, M1907I, has been reported in the Human Gene Mutation Database in association with ATRX-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we interpret D1908Y as a variant of uncertain significance.

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