ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.3417+1G>A

dbSNP: rs587779444
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000442138 SCV000511436 pathogenic not provided 2016-12-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000087369 SCV001585876 pathogenic Ehlers-Danlos syndrome, type 4 2023-12-26 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 46 of the COL3A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Ehlers-Danlos syndrome (PMID: 22019127, 24922459; Invitae). ClinVar contains an entry for this variant (Variation ID: 101132). Studies have shown that disruption of this splice site results in skipping of exon 46, but is expected to preserve the integrity of the reading-frame (PMID: 22019127). This variant disrupts the triple helix domain of COL3A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL3A1, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000087369 SCV003928694 pathogenic Ehlers-Danlos syndrome, type 4 2023-04-25 criteria provided, single submitter clinical testing Variant summary: COL3A1 c.3417+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing and results in the in-frame skipping of exon 46 (e.g. PMID:22019127). This is expected to affect the triple-helical region of the encoded protein and alterations of glycine residues within the collagen triple-helix are common mechanisms of disease. The variant was absent in 251444 control chromosomes (gnomAD). c.3417+1G>A has been reported in the literature in individuals affected with Ehlers-Danlos Syndrome, Vascular Type (PMID: 22019127, 24922459). These data indicate that the variant is likely associated with disease. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Collagen Diagnostic Laboratory, University of Washington RCV000087369 SCV000120251 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing

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