Submissions for variant NM_014244.5(ADAMTS2):c.2480G>A (p.Arg827Gln)

gnomAD frequency: 0.02575  dbSNP: rs35445112

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000308254	SCV000456849	likely benign	Ehlers-Danlos syndrome, dermatosparaxis type	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000432102	SCV000520363	benign	not specified	2016-10-31	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000308254	SCV000647122	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2025-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000432102	SCV001482103	benign	not specified	2021-02-22	criteria provided, single submitter	clinical testing	Variant summary: ADAMTS2 c.2480G>A (p.Arg827Gln) results in a conservative amino acid change located in the ADAM-TS Spacer 1 domain (IPR010294) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.026 in 251048 control chromosomes in the gnomAD database, including 126 homozygotes. The observed variant frequency is approximately 9- fold 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, there are no reports of of c.2480G>A in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating an impact on protein function published in the literature. Four 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/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278591	SCV002565634	benign	Ehlers-Danlos syndrome	2022-07-16	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV004707139	SCV005222624	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000308254	SCV001457876	benign	Ehlers-Danlos syndrome, dermatosparaxis type	2020-09-16	no assertion criteria provided	clinical testing