Submissions for variant NM_000090.4(COL3A1):c.1051-13G>A

gnomAD frequency: 0.00093  dbSNP: rs371934572

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181048	SCV000233323	benign	not specified	2014-08-22	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.
Illumina Laboratory Services, Illumina	RCV000396576	SCV000425507	likely benign	Ehlers-Danlos syndrome, type 4	2016-06-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000181048	SCV000711507	likely benign	not specified	2016-04-21	criteria provided, single submitter	clinical testing	c.1051-13G>A in intron 15 of COL3A1: This variant is not expected to have clinic al significance because it has been identified in 0.37% (11/3000) of African chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs371934572).
Color Diagnostics, LLC DBA Color Health	RCV001188352	SCV001355397	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-12-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181048	SCV001821349	benign	not specified	2021-08-23	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.1051-13G>A 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. 2/2 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 0.00085 in 150898 control chromosomes, predominantly at a frequency of 0.003 within the African or African-American subpopulation in the gnomAD database (v3.1 genomes dataset), including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2000 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Ehlers-Danlos Syndrome, Vascular Type phenotype (1.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1051-13G>A in individuals affected with Ehlers-Danlos Syndrome, Vascular Type and no experimental evidence demonstrating its impact on protein function have been reported. Three 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000396576	SCV002443825	benign	Ehlers-Danlos syndrome, type 4	2024-01-31	criteria provided, single submitter	clinical testing