ClinVar Miner

Submissions for variant NM_014244.5(ADAMTS2):c.991G>A (p.Glu331Lys) (rs17667857)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000301183 SCV000456875 uncertain significance Ehlers-Danlos syndrome dermatosparaxis type 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000498059 SCV000590497 uncertain significance not provided 2019-01-21 criteria provided, single submitter clinical testing The E331K variant of uncertain significance in the ADAMTS2 gene has not been published as pathogenic or been reported as benign to our knowledge. E331K was observed in 3/11,456 (0.03%) alleles from individuals of Latino ancestry in the Exome Aggregation Consortium (Lek et al., 2016). The E331K 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. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants.
Invitae RCV000301183 SCV000936219 uncertain significance Ehlers-Danlos syndrome dermatosparaxis type 2019-10-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 331 of the ADAMTS2 protein (p.Glu331Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs17667857, ExAC 0.03%). This variant has not been reported in the literature in individuals with ADAMTS2-related disease. ClinVar contains an entry for this variant (Variation ID: 353127). 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 disruptive, but 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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