ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.2771G>A (p.Gly924Asp)

dbSNP: rs587779450
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002433595 SCV002747208 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2018-09-17 criteria provided, single submitter clinical testing The p.G924D variant (also known as c.2771G>A), located in coding exon 39 of the COL3A1 gene, results from a G to A substitution at nucleotide position 2771. The glycine at codon 924 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 variant has been reported in a vascular Ehlers-Danlos syndrome (EDS) cohort, and has been detected in a patient with features consistent with vascular EDS (Pepin MG et al. Genet Med. 2014;16:881-8; Weerakkody RA et al. Genet Med. 2016; 11;18:1119-1127). 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). In addition, other alterations in the same codon (G924S (c.2770G>A), G924V (c.2771G>T), and G924C (c.2770G>T)) have also been detected in vascular EDS cohorts (Pepin MG et al. Genet. Med., 2014;16:881-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Collagen Diagnostic Laboratory, University of Washington RCV000087376 SCV000120258 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing

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