ClinVar

Description

The p.G222D pathogenic mutation (also known as c.665G>A), located in coding exon 8 of the COL3A1 gene, results from a G to A substitution at nucleotide position 665. The glycine at codon 222 is replaced by aspartic acid, an amino acid with 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 reported in several Ehlers-Danlos syndrome type IV (EDS, vascular type) cohorts (Ferré FC et al. BMJ Open. 2012;2:e000705; Pepin MG et al. Genet. Med. 2014;16:881-8). This mutation has been determined to be the result of a de novo mutation or germline mosaicism in one individual with EDS (Ambry internal data). Internal structural analysis has demonstrated 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). A likely pathogenic alteration in the same codon, p.G222V, has also been described (Morissette R et al. Circ Cardiovasc Genet. 2014;7:80-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.