ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1347+1G>A

dbSNP: rs397509370
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000087697 SCV000940573 pathogenic Ehlers-Danlos syndrome, type 4 2022-10-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as 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: 17202). This variant is also known as G+1 IVS20 and c.1347+1G>A/IVS 19. Disruption of this splice site has been observed in individuals with Ehlers–Danlos syndrome (PMID: 2349939, 24399159, 24922459, 27306637, 30474650). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor 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).
Color Diagnostics, LLC DBA Color Health RCV001184539 SCV001350547 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2021-01-06 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +1 position of intron 19 of the COL3A1 gene. An RNA study has shown that this variant causes complex aberrant splicing due to in-frame skipping of an exon and a use of cryptic splice donor site that leads to in-frame insertion of 24 nucleotides (PMID: 2349939). This variant is a recurrent mutation in individuals affected with vascular Ehlers–Danlos syndrome (PMID: 24399159, 24922459, 27306637, 27462043, 30919682, 31600821). This variant has also been reported in an individual affected with aortic aneurysms that ruptured and resulted in death (PMID: 2349939). A study using fibroblasts from this individual has shown a decrease in pepsin-resistant type Ill procollagen in the cells (PMID: 2349939). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
GeneDx RCV001753421 SCV001986095 pathogenic not provided 2021-10-26 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); Reported as pathogenic by other clinical laboratories in ClinVar (ClinVar Variant ID# 17202; Landrum et al., 2016); Canonical splice site variant expected to result in aberrant splicing; Multiple functional studies demonstrate that c.1347+1 G>A results in a complex splice outcome that includes skipping of exon 19, retention of intron 19, and use of a cryptic splice donor site that leads to insertion of the first 24 nucleotides of intron 19 (Kontusaari et al., 1990; Anderson et al., 1997); Aberrant splicing is a common mechanism of disease in this gene (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27306637, 22019127, 2349939, 24922459, 17251678, 21219851, 9143932, 30474650, 27462043, 30919682, 31600821)
Ambry Genetics RCV001184539 SCV002690266 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-01-23 criteria provided, single submitter clinical testing The c.1347+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 19 of the COL3A1 gene. This alteration has been reported in association with Ehlers-Danlos syndrome type IV (vascular type) and related features and has also been shown to result in abnormal splicing (Kontusaari S et al. ;Am J Hum Genet. 1990;47(1):112-20; Watanabe A et al. Circ J. 2007;71(2):261-5; Drera B et al. J Dermatol Sci. 2011;64(3):237-40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic RCV001753421 SCV005413540 pathogenic not provided 2023-12-07 criteria provided, single submitter clinical testing PP1, PP3, PP4, PM2, PS3, PS4_moderate, PVS1_strong
OMIM RCV000087697 SCV000039025 pathogenic Ehlers-Danlos syndrome, type 4 1990-07-01 no assertion criteria provided literature only
Collagen Diagnostic Laboratory, University of Washington RCV000087697 SCV000120589 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004532389 SCV004743202 pathogenic COL3A1-related disorder 2023-11-07 no assertion criteria provided clinical testing The COL3A1 c.1347+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the heterozygous state in multiple individuals with vascular Ehlers-Danlos syndrome (see for example, Cazzato et al. 2016. PubMed ID: 27306637; Li et al. 2022. PubMed ID: 36119745; reported as G+1 IVS20 in Kontusaari et al. 1990. PubMed ID: 2349939). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in COL3A1 are expected to be pathogenic. This variant is interpreted as pathogenic.

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