Submissions for variant NM_014244.5(ADAMTS2):c.534+9G>C

gnomAD frequency: 0.33886  dbSNP: rs2271213

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000278093	SCV000456889	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.
GeneDx	RCV000432760	SCV000520266	benign	not specified	2016-09-29	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	RCV000432760	SCV000916418	benign	not specified	2018-06-29	criteria provided, single submitter	clinical testing	Variant summary: ADAMTS2 c.534+9G>C 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. 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 0.42 in 105062 control chromosomes in the ExAC database, including 9072 homozygotes. The observed variant frequency is approximately 144-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.534+9G>C in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000278093	SCV001730536	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2025-02-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000278093	SCV001762781	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2021-07-10	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000278093	SCV000734403	benign	Ehlers-Danlos syndrome, dermatosparaxis type		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000278093	SCV000745667	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2014-02-04	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000278093	SCV001458936	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2020-09-16	no assertion criteria provided	clinical testing