ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1509+2T>C

gnomAD frequency: 0.00003  dbSNP: rs1553508039
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000608512 SCV000731708 likely pathogenic Ehlers-Danlos syndrome, type 4 2017-10-09 criteria provided, single submitter clinical testing The c.1509+2T>C variant in COL3A1 has not been previously reported in individual s with Ehlers-Danlos syndrome (EDS) type IV (vascular type) or in large populati on studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abno rmal or absent protein. The spectrum of reported pathogenic COL3A1 variants incl udes splice variants with genotype-phenotype correlations showing a more severe effect when the effect is exon skipping (versus loss of function, which is assoc iated with a milder presentation: Pepin 2015, GeneReviews: https://www.ncbi.nlm. nih.gov/books/NBK1494/). In summary, although additional studies are required to fully establish its clinical significance, the c.1509+2T>C variant is likely pa thogenic.
Color Diagnostics, LLC DBA Color Health RCV001179402 SCV001344057 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2019-08-14 criteria provided, single submitter clinical testing This variant alters the canonical splice donor position in intron 21 of the COL3A1 gene. Computational splicing tools predict that this variant may have a significant impact on RNA splicing. Although RNA study has not been performed to confirm the prediction, this variant is expected to result in a disrupted protein product. To our knowledge, This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of COL3A1 function is a known mechanism of disease. Based on available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000608512 SCV003274793 likely pathogenic Ehlers-Danlos syndrome, type 4 2022-08-30 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 517434). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 21 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).

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