ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.636+5G>A (p.Gly195_Ser212del) (rs587779688)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc RCV000087686 SCV000781224 pathogenic Ehlers-Danlos syndrome, type 4 2016-11-01 criteria provided, single submitter clinical testing
Collagen Diagnostic Laboratory,University of Washington RCV000087686 SCV000120578 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing
Invitae RCV000087686 SCV000825586 pathogenic Ehlers-Danlos syndrome, type 4 2018-05-03 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the COL3A1 gene. It does not directly change the encoded amino acid sequence of the COL3A1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Ehlers-Danlos syndrome, vascular type (PMID: 9399899, 12131463, 24399159). This variant is also described as IVS8+5G>A in the literature.  ClinVar contains an entry for this variant (Variation ID: 101448). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant results in exon skipping, leading to an in-frame deletion of exon 7, also reported as exon 8 in the literature (PMID: 9399899, 12131463). This splicing variant leads to a deletion of exon 7, which is expected to disrupt glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain that are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL3A1, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC).  This suggests loss of these residues may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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