ClinVar Miner

Submissions for variant NM_014244.5(ADAMTS2):c.1883G>A (p.Arg628His) (rs140621260)

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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 RCV000331977 SCV000456864 uncertain significance Ehlers-Danlos syndrome dermatosparaxis type 2018-01-12 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 RCV000431482 SCV000531939 uncertain significance not specified 2017-08-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ADAMTS2 gene. The R628H variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 94/87886 (0.1%) alleles from individuals of European (non-Finnish) background, in 11/24106 (0.05%) alleles from individuals of South Asian background and in 11/18124 (0.06%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The R628H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Although this substitution occurs at a position that is conserved in mammals, in silico predicts this variant likely does not alter the protein structure/function.
Invitae RCV000331977 SCV000647111 uncertain significance Ehlers-Danlos syndrome dermatosparaxis type 2019-12-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 628 of the ADAMTS2 protein (p.Arg628His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs140621260, ExAC 0.2%), including one homozygous individual. This variant has not been reported in the literature in individuals with ADAMTS2-related disease. ClinVar contains an entry for this variant (Variation ID: 353118). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; 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.

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