ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1348-2A>G

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003634140 SCV004536954 pathogenic Ehlers-Danlos syndrome, type 4 2024-08-28 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 19 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 individual(s) with vascular Ehlers-Danlos syndrome (PMID: 30474650, 31575845). In at least one individual the variant was observed to be de novo. 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.
All of Us Research Program, National Institutes of Health RCV003634140 SCV005427293 likely pathogenic Ehlers-Danlos syndrome, type 4 2024-06-27 criteria provided, single submitter clinical testing This variant causes an A>G nucleotide substitution at the -2 position of intron 19 of the COL3A1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in two individuals affected with vascular Ehlers Danlos syndrome (PMID: 30474650, 31575845), including one instance reported to occur as a de novo event (PMID: 30474650). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of COL3A1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.

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