Submissions for variant NM_014244.5(ADAMTS2):c.724G>A (p.Ala242Thr)

gnomAD frequency: 0.00026  dbSNP: rs372103269

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000290119	SCV000456883	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.
CeGaT Center for Human Genetics Tuebingen	RCV000415769	SCV000493398	uncertain significance	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000290119	SCV000824874	uncertain significance	Ehlers-Danlos syndrome, dermatosparaxis type	2022-08-14	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 242 of the ADAMTS2 protein (p.Ala242Thr). This variant is present in population databases (rs372103269, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 353135). 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, which suggests that this missense change does not adversely affect protein function. 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	RCV000415769	SCV001822601	likely benign	not provided	2020-04-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; The A242T has been reported as a variant of uncertain significance by other laboratories in ClinVar (SCV000493398.5; SCV000824874.1; Landrum et al., 2016).
Mayo Clinic Laboratories, Mayo Clinic	RCV000415769	SCV002542150	uncertain significance	not provided	2021-09-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278603	SCV002565978	uncertain significance	Ehlers-Danlos syndrome	2022-08-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000290119	SCV001462994	likely benign	Ehlers-Danlos syndrome, dermatosparaxis type	2020-04-20	no assertion criteria provided	clinical testing