ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.997-1G>C

dbSNP: rs587779687
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181075 SCV000233351 pathogenic not provided 2023-11-29 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24922459)
Ambry Genetics RCV001190410 SCV000738544 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-05-02 criteria provided, single submitter clinical testing The c.997-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 15 of the COL3A1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This variant was detected in a patient from a study of vascular Ehlers-Danlos syndrome clinical genetic testing; however, clinical details were limited (Pepin MG et al. Genet. Med., 2014 Dec;16:881-8). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with COL3A1-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health RCV001190410 SCV001357890 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2019-01-14 criteria provided, single submitter clinical testing This variant alters the canonical splice acceptor site in intron 14 of the COL3A1 gene. Computational splicing tools predict that this variant may have a significant adverse impact on RNA splicing. Although, to our knowledge, RNA study has not been performed to confirm the prediction, this variant is expected to result in a disrupted protein product. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same splice acceptor site, c.997-2A>G, has been reported in three related individuals in one family affected with vascular Ehlers-Danlos syndrome (PMID: 24399159). Based on available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000087685 SCV001576694 pathogenic Ehlers-Danlos syndrome, type 4 2023-12-07 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 14 of the COL3A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL3A1 are known to be pathogenic (PMID: 24922459). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with COL3A1-related conditions (PMID: 24399159, 24922459, 30793832, 30919682; Invitae). ClinVar contains an entry for this variant (Variation ID: 101447). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Collagen Diagnostic Laboratory, University of Washington RCV000087685 SCV000120577 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing

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