ClinVar Genomic variation as it relates to human health

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.

Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with vascular Ehlers-Danlos syndrome. Haploinsufficiency as a result of null alleles appears to confer delayed onset, and milder clinical course (PMID: 2934645; 21637106). Dominant-negative as a result of missense variants affecting glycine residues in the Gly-X-Y repeat within the triple helical region (PMID: 2934645). (I) 0108 - This gene is associated with both recessive and dominant disease. Vascular Ehlers-Danlos syndrome (EDS), AD; Polymicrogyria with or without vascular EDS, AR (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid (exon 8). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a moderate amino acid change. (SP) 0601 - Variant is located in the well-established functional collagen triple helix domain and affecting the glycine of the G-X-Y repeats (PDB). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with vascular Ehlers-Danlos syndrome (ClinVar, PMID: 22492385, 29940997, 30474650). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign