Thoracic aortic aneurysm or dissection

Gene: COL1A1

After consulting with the Genomics England Clinical Team, it was decided that this gene should remain Green on this panel.

Created: 13 Jan 2020, 10:40 a.m. | Last Modified: 13 Jan 2020, 10:40 a.m.

Panel Version: 1.110

Red List (low evidence)

Gene not currently tested on Manchester cardiac gene panel. 1066 variants listed on HGMD (accessed 24/09/2019). ClinGen Knowledge Base: association with osteogenesis imperfecta type 1 (accessed 24/09/2019). Very little literature showing aortic involvement.

Created: 24 Sep 2019, 1:56 p.m. | Last Modified: 24 Sep 2019, 1:56 p.m.

Panel Version: 1.93

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• 14630726

I don't know

Associated with EDS and OI, which overlap with TAAD.
Present on Wessex aortopathy panel, but no pathogenic or likely pathogenic variants have been detected in patients referred specifically for aortopathy (without other COL1A1 specific syndromic features e.g. OI).

Created: 8 May 2019, 12:45 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

130060 AD Ehler's Danlos syndrome arthrochalasia type 1, which does not have a cardiac/aortopathy phenotype associated on OMIM; gene also causative of osteogeneisis imperfecta. Should this be included as it is similar situation to some of the red genes - involved in CTD but without aortopathy.

Created: 25 Mar 2019, 4:30 p.m.

Weerakkody et al 2016 Genet Med 18:1119 PMID:27011056 is one of several publications identifying variants in COL1A1 in EDS patients. One frameshift and two missense (affecting glycine in the G-X-Y collagen triple-helix motif) variants are described: c.1265delG: p.Gly422AlafsX119; c.643G>A: p.Gly215Ser; c.662G>C: p.Gly221Ala. None of these have any gnomAD frequency.

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

PMID:26188975 perform WES in 102 TAAD patients using a 21-gene panel including COL1A1, COL1A2 and COL5A2: 2 patients had suspicious variants of unknown significance in COL1A1- V349F (previously reported in association with OI) and N1394S.

Created: 29 Jun 2017, 11:30 a.m.

COL1A1 is on this panel for syndromic TAAD: patients with syndromic thoracic aortic aneurysm suffer from conditions including Ehlers-Danlos syndrome (EDS). Osteogenesis Imperfecta (OI) patients can also present with TAAD as a secondary feature (PMID:10523481).

Created: 29 Jun 2017, 11:30 a.m.

Comment when marking as ready: Definite disease-causing gene, with phenotype overlapping Thoracic Aortic Aneurysm Disease

Created: 19 Feb 2016, 2:39 p.m.

Green List (high evidence)

Mice with a deletion in the first intron of the Col1a1 gene develop age-dependent aortic dissection and rupture (PMID: 14630726). Lower incidence of TAAD in humans harbouring COL1A1 mutations (PMID: 14630726)

Created: 12 Feb 2016, 11 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
#130000- Ehlers-Danlos syndrome, classic; #130060- Ehlers-Danlos syndrome, type VIIA

Publications

• PMID: 14630726
• 26188975

I don't know

This gene was part of an initial gene list collated by Matthew Edwards Royal Brompton Hospital sent 16th Jan 2019 on behalf of the London South GLH for review by the GMS Cardiology Specialist Group. Only gene symbol from the Royal Brompton gene panel was provided - suggested initial gene rating and evidence for inclusion not provided with the list.

Created: 20 Feb 2019, 2:17 p.m.

Not on the Inherited Cardiac Condition Genes panel for Familial aortic anuerysm reported in: Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes, Pua et al, Journal of Cardiovascular Translational Research, online Feb 2016 (doi:10.​1007/​s12265-016-9673-5). The panel contains disease-causing, putatively pathogenic, research and phenocopy genes.

Created: 19 Feb 2016, 10:54 a.m.

Comment on phenotypes: Sourced from OMIM

Created: 1 Feb 2016, 11:29 a.m.