ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.322+1G>C

gnomAD frequency: 0.00014  dbSNP: rs770598613
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196203 SCV000249999 uncertain significance not provided 2022-04-12 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 31538843)
Blueprint Genetics RCV000196203 SCV000927946 likely pathogenic not provided 2018-09-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV002444789 SCV002612230 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-11-26 criteria provided, single submitter clinical testing The c.322+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 2 of the COL5A2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of COL5A2 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV003758721 SCV004380465 likely pathogenic Ehlers-Danlos syndrome, classic type, 1 2023-09-06 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: 213136). Disruption of this splice site has been observed in individual(s) with intracranial aneurysm (PMID: 31538843). This variant is present in population databases (rs770598613, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This sequence change affects a donor splice site in intron 2 of the COL5A2 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 COL5A2 are known to be pathogenic (PMID: 23587214).

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