ClinVar Miner

Submissions for variant NM_014244.5(ADAMTS2):c.2272G>A (p.Ala758Thr) (rs146222244)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000762249 SCV000892537 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
GeneDx RCV000762249 SCV000619588 uncertain significance not provided 2018-05-08 criteria provided, single submitter clinical testing The A758T variant of uncertain significance in the ADAMTS2 gene has not been published as pathogenic or benign to our knowledge. The A758T 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In addition, A758T is observed in 0.06% (81/126,632) of alleles from individuals of European (non-Finnish) background in large population cohorts, although no homozygotes are reported (Lek et al., 2016).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000646241 SCV000768004 uncertain significance Ehlers-Danlos syndrome, type vii, autosomal recessive 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 758 of the ADAMTS2 protein (p.Ala758Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs146222244, ExAC 0.06%). This variant has not been reported in the literature in individuals with ADAMTS2-related disease. ClinVar contains an entry for this variant (Variation ID: 450954). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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