Submissions for variant NM_014244.5(ADAMTS2):c.119CCG[5] (p.Ala43dup)

dbSNP: rs1174228917

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001697344	SCV000714735	likely benign	not provided	2022-03-16	criteria provided, single submitter	clinical testing
Invitae	RCV001243792	SCV001416975	uncertain significance	Ehlers-Danlos syndrome, dermatosparaxis type	2022-08-31	criteria provided, single submitter	clinical testing	This variant, c.128_130dup, results in the insertion of 1 amino acid(s) of the ADAMTS2 protein (p.Ala43dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ADAMTS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 506648). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279388	SCV002565767	uncertain significance	Ehlers-Danlos syndrome	2021-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330822	SCV004038441	uncertain significance	not specified	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: ADAMTS2 c.128_130dupCCG (p.Ala43dup) results in an in-frame duplication that is predicted to duplicate one amino acid in the encoded protein. 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 0.0016 in 145858 control chromosomes (no homozygotes), predominantly at a frequency of 0.0057 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ADAMTS2 causing Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) phenotype (0.0029), suggesting that the variant nay be a benign polymorphism found primarily in populations of African or African-American origin. However, the variant is noted to occur in a low complexity region (gnomAD) and therefore this allele frequency may not be reliable. To our knowledge, no occurrence of c.128_130dupCCG in individuals affected with Ehlers-Danlos Syndrome, Type VIIC (Dermatosparaxis) and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments; two submitters classified the variant as uncertain significance, and two submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Natera, Inc.	RCV001243792	SCV001458940	likely benign	Ehlers-Danlos syndrome, dermatosparaxis type	2020-09-16	no assertion criteria provided	clinical testing