Submissions for variant NM_014244.5(ADAMTS2):c.2028C>T (p.Asp676=)

gnomAD frequency: 0.24390  dbSNP: rs1972715

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000331878	SCV000456861	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000431081	SCV000520274	benign	not specified	2016-09-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000431081	SCV000916419	benign	not specified	2018-07-05	criteria provided, single submitter	clinical testing	Variant summary: ADAMTS2 c.2028C>T results in a synonymous change. The variant allele was found at a frequency of 0.22 in 120712 control chromosomes in the ExAC database, including 3229 homozygotes. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.23 in 276950 control chromosomes in the gnomAD database, including 7555 homozygotes. The observed variant frequency is approximately 78-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in ADAMTS2 causing Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) phenotype (0.0029), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2028C>T in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "benign." Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV000331878	SCV001623494	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2021-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000331878	SCV001730539	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2025-02-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000331878	SCV001457882	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2020-09-16	no assertion criteria provided	clinical testing