Cerebral vascular malformations

Gene: COL5A1

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 6 Dec 2024, 10:20 a.m. | Last Modified: 6 Dec 2024, 10:20 a.m.

Panel Version: 3.18

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Comment on mode of inheritance: There is sufficient evidence available for the association of heterozygous COL5A1 variants with this panel. However, there are only two cases reported with compound heterozygous variants. Hence the MOI should be set as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.

Created: 12 Apr 2024, 9:51 p.m. | Last Modified: 12 Apr 2024, 9:51 p.m.

Panel Version: 3.14

PMID:17053184 - Of 15 patients from seven families with spontaneous cervical artery dissections (CAD) recruited in this study, two patients from a family carried a rare variant in COL5A1 (p.Asp192Asn). One of them also carried a rare variant in COL5A2.

PMID:31903434 - Among 43 patients with cervical artery dissection (CeAD) analysed in this study, one patient had classic Ehlers Danlos syndrome due to two different missense variants in COL5A1 (p.Arg65Trp and p.Val172Phe), while another patient had missense variants in COL5A2 (p.Pro1103Leu) and COL5A1 (p.Thr1757Met).

PMID:32938213 - Four unrelated individuals were reported with the same heterozygous variant in COL5A1 (p.Gly514Ser) and they presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. The existence of a common haplotype among all four probands suggest founder effect.

PMID:33189937 - A 22-year-old patient with intracranial aneurysm and mild connective tissue manifestations reminiscent of EDS was identified with two COL5A1 missense variants in trans configuration (p.Gly530Ser and p.Pro1379Ser).

PMID:35911880 - A female was reported with postpartum arterial dissection involving all four cervicocephalic arteries resulting in acute cerebral infarction. She was identified with a heterozygous COL5A1 gene variant (p.Asp1648Gly).

This gene has been associated with relevant phenotypes in OMIM and Gene2Phenotype.

Created: 12 Apr 2024, 9:30 p.m. | Last Modified: 12 Apr 2024, 9:41 p.m.

Panel Version: 3.11

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Ehlers-Danlos syndrome, classic type, 1, OMIM:130000; Fibromuscular dysplasia, multifocal, OMIM:619329

Publications

• 17053184
• 31903434
• 32938213
• 33189937
• 35911880

Green List (high evidence)

PMID: 32938213 describe 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries.
Enough evidence for green. Other mFMD included in the panel.
Sources: Radboud University Medical Center, Nijmegen

Created: 19 Jan 2024, 8:47 a.m. | Last Modified: 19 Jan 2024, 8:48 a.m.

Panel Version: 3.9

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Fibromuscular dysplasia, multifocal

Publications

• PMID: 32938213

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments