Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
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. |
Prevention |
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, |
RCV000087552 | SCV000120439 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |