ClinVar Miner

Submissions for variant NM_014244.5(ADAMTS2):c.2846A>C (p.Asn949Thr)

gnomAD frequency: 0.00353  dbSNP: rs376054177
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001154262 SCV001315603 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001154262 SCV001415736 uncertain significance Ehlers-Danlos syndrome, dermatosparaxis type 2020-06-14 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 949 of the ADAMTS2 protein (p.Asn949Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is present in population databases (rs376054177, ExAC 0.02%). This variant has not been reported in the literature in individuals with ADAMTS2-related disease. 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.
GeneDx RCV001593296 SCV001823460 uncertain significance not provided 2019-11-15 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Mayo Clinic Laboratories, Mayo Clinic RCV001593296 SCV005411958 uncertain significance not provided 2024-04-11 criteria provided, single submitter clinical testing BP4
Natera, Inc. RCV001154262 SCV002081911 uncertain significance Ehlers-Danlos syndrome, dermatosparaxis type 2020-02-13 no assertion criteria provided clinical testing

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