Submissions for variant NM_014244.5(ADAMTS2):c.1629+9G>A

gnomAD frequency: 0.00560  dbSNP: rs115550684

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000377406	SCV000332641	benign	not specified	2015-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001705407	SCV000528963	benign	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558463	SCV000647106	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2025-02-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000558463	SCV001318390	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000377406	SCV001338290	benign	not specified	2020-02-09	criteria provided, single submitter	clinical testing	Variant summary: ADAMTS2 c.1629+9G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 0.0079 in 251094 control chromosomes in the gnomAD database, including 13 homozygotes. The observed variant frequency is approximately 2.74 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 benign. To our knowledge, no occurrence of c.1629+9G>A 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. All laboratories classified the variant as benign (n=2)/likely benign(n=1). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278265	SCV002565457	benign	Ehlers-Danlos syndrome	2022-06-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000558463	SCV002798095	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2022-02-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000558463	SCV002084183	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2019-12-09	no assertion criteria provided	clinical testing