Submissions for variant NM_014244.5(ADAMTS2):c.710A>C (p.Asp237Ala)

gnomAD frequency: 0.00011  dbSNP: rs202197821

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000376606	SCV000456885	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	RCV000659043	SCV000581874	uncertain significance	not provided	2018-12-19	criteria provided, single submitter	clinical testing	The D237A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 23/126402 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the D237A 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.
CeGaT Center for Human Genetics Tuebingen	RCV000659043	SCV000780847	uncertain significance	not provided	2018-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000376606	SCV000895692	uncertain significance	Ehlers-Danlos syndrome, dermatosparaxis type	2018-10-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278604	SCV002565967	uncertain significance	Ehlers-Danlos syndrome	2021-06-17	criteria provided, single submitter	clinical testing
Invitae	RCV000376606	SCV003253242	uncertain significance	Ehlers-Danlos syndrome, dermatosparaxis type	2022-05-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 237 of the ADAMTS2 protein (p.Asp237Ala). This variant is present in population databases (rs202197821, gnomAD 0.02%). 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: 353137). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000659043	SCV004227172	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BP4
Natera, Inc.	RCV000376606	SCV001462995	uncertain significance	Ehlers-Danlos syndrome, dermatosparaxis type	2020-04-20	no assertion criteria provided	clinical testing