Submissions for variant NM_000090.4(COL3A1):c.3525+19del

gnomAD frequency: 0.01120  dbSNP: rs138061246

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181062	SCV000233338	benign	Familial thoracic aortic aneurysm and aortic dissection	2013-01-17	criteria provided, single submitter	clinical testing	The variant is found in TAAD panel(s).
PreventionGenetics, part of Exact Sciences	RCV000242246	SCV000302044	benign	not specified		criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659430	SCV000781244	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000242246	SCV001361057	benign	not specified	2019-08-19	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.3525+19delG alters a 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 0.0099 in 228966 control chromosomes, predominantly at a frequency of 0.016 within the Non-Finnish European subpopulation in the gnomAD database, including 14 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12800-folds over the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.3525+19delG in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812164	SCV001473616	benign	not provided	2024-11-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002054162	SCV002340019	benign	Ehlers-Danlos syndrome, type 4	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000181062	SCV002614032	benign	Familial thoracic aortic aneurysm and aortic dissection	2019-08-22	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.