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

gnomAD frequency: 0.00353  dbSNP: rs376054177

Total submissions: 4

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.
Invitae	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
Natera, Inc.	RCV001154262	SCV002081911	uncertain significance	Ehlers-Danlos syndrome, dermatosparaxis type	2020-02-13	no assertion criteria provided	clinical testing