Submissions for variant NM_000090.4(COL3A1):c.1816-4T>C

gnomAD frequency: 0.00003  dbSNP: rs765128089

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000866672	SCV001007800	likely benign	Ehlers-Danlos syndrome, type 4	2024-09-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001185341	SCV001351536	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001585822	SCV001812419	likely benign	not provided	2018-12-04	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279575	SCV002565611	uncertain significance	Ehlers-Danlos syndrome	2019-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235422	SCV003934192	uncertain significance	not specified	2023-05-01	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.1816-4T>C alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 1.2e-05 in 251314 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1816-4T>C in individuals affected with Ehlers-Danlos Syndrome, Vascular Type and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as Likely Benign (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004538243	SCV004735110	likely benign	COL3A1-related disorder	2021-01-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).