ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1869+1G>C

dbSNP: rs587779600
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000087552 SCV001375279 pathogenic Ehlers-Danlos syndrome, type 4 2019-10-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL3A1 are known to be pathogenic (PMID: 24922459). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 20518783, 23293852). Disruption of this splice site has been observed in individuals with clinical features of vascular Ehlers Danlos syndrome (PMID: 23293852, 20518783, 24922459, Invitae). This variant is also known as g.IVS27+1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 101314). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 26 of the COL3A1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
PreventionGenetics, part of Exact Sciences RCV004529909 SCV004114245 pathogenic COL3A1-related disorder 2022-10-12 criteria provided, single submitter clinical testing The COL3A1 c.1869+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in individuals with autosomal dominant Ehlers-Danlos syndrome IV (vascular type) (Table 1, referred to as IVS27+1G>C, Shimaoka et al. 2010. PubMed ID: 20518783; Table S1, Pepin et al. 2014. PubMed ID: 24922459). In vitro studies using patient derived fibroblasts revealed a significant reduction in type III collagen production (Table 1, referred to as IVS27+1G>C, Shimaoka et al. 2010. PubMed ID: 20518783). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Alternate nucleotide changes at this position (c.1869+1G>A and c.1869+1G>T) have also been reported in individuals with autosomal dominant Ehlers-Danlos syndrome IV (vascular type) (referred to as IVS27+1G>A, Shimaoka et al. 2013. PubMed ID: 23293852; Table S2, Legrand et al. 2019. PubMed ID: 30474650). Variants that disrupt the consensus splice donor site in COL3A1 are expected to be pathogenic. The c.1869+1G>C variant is interpreted as pathogenic.
Collagen Diagnostic Laboratory, University of Washington RCV000087552 SCV000120439 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing

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