Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002444561 | SCV002736281 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2023-04-10 | criteria provided, single submitter | clinical testing | The p.G762D pathogenic mutation (also known as c.2285G>A), located in coding exon 33 of the COL3A1 gene, results from a G to A substitution at nucleotide position 2285. The glycine at codon 762 is replaced by aspartic acid, an amino acid with some similar properties. The majority (approximately two-thirds) of COL3A1 mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (Pepin MG et al. Genet Med. 2014;16(12):881-8; Frank M et al. Eur J Hum Genet. 2015;23(12):1657-64). This particular glycine substitution has been detected in several individuals reported to have vascular Ehlers-Danlos syndrome, including a report of a de novo occurrence (Ferré FC et al. BMJ Open. 2012;2:e000705; Morissette R et al. Circ Cardiovasc Genet. 2014;7:80-8; Frank M. Eur J Hum Genet. 2015;23(12):1657-64; Legrand A. Genet Med. 2019 07;21(7):1568-1575). Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif in the COL3A1 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Gene |
RCV004700410 | SCV005202098 | pathogenic | not provided | 2024-02-20 | criteria provided, single submitter | clinical testing | Reported in association with vascular Ehlers-Danlos syndrome (PMID: 22492385, 24399159); Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24399159, 30474650, 22492385, 10706896, 9036918) |
| Collagen Diagnostic Laboratory, |
RCV000087615 | SCV000120506 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |