Submissions for variant NM_014244.5(ADAMTS2):c.1458C>T (p.Tyr486=)

gnomAD frequency: 0.00427  dbSNP: rs61757478

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000347202	SCV000456867	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV001171974	SCV000527963	benign	not provided	2018-07-31	criteria provided, single submitter	clinical testing
Invitae	RCV000347202	SCV000647104	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000431781	SCV000918394	benign	not specified	2018-12-26	criteria provided, single submitter	clinical testing	Variant summary: ADAMTS2 c.1458C>T alters a conserved nucleotide resulting in a synonymous change. 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 0.0046 in 272964 control chromosomes, including 7 homozygotes (gnomAD). The observed variant frequency within Finnish control individuals (0.018) in the gnomAD database is approximately 6-fold of 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 a benign polymorphism. To our knowledge, no occurrence of c.1458C>T in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2 classifying it as benign/likely benign and 1 as VUS). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV001171974	SCV001334897	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ADAMTS2: BP4, BP7
Genome-Nilou Lab	RCV000347202	SCV001737251	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2021-05-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278598	SCV002566322	benign	Ehlers-Danlos syndrome	2022-04-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000347202	SCV002084191	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2019-10-18	no assertion criteria provided	clinical testing