Submissions for variant NM_014244.5(ADAMTS2):c.722G>A (p.Arg241His)

dbSNP: rs11750821

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000321964	SCV000456884	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	RCV000442585	SCV000520267	benign	not specified	2016-10-06	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	RCV000442585	SCV000918396	benign	not specified	2018-04-30	criteria provided, single submitter	clinical testing	Variant summary: ADAMTS2 c.722G>A (p.Arg241His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.087 in 276330 control chromosomes in the gnomAD database, including 1197 homozygotes. The observed variant frequency is approximately 30-fold 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.722G>A in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaulation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000321964	SCV001730535	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000321964	SCV001762779	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2021-07-10	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000321964	SCV000734402	benign	Ehlers-Danlos syndrome, dermatosparaxis type		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000321964	SCV000745666	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2014-02-04	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000321964	SCV001458931	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2020-09-16	no assertion criteria provided	clinical testing