ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.638G>A (p.Gly213Asp)

dbSNP: rs2153501864
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV001508125 SCV001714066 likely pathogenic not provided 2020-02-05 criteria provided, single submitter clinical testing PM1, PM2, PM5, PM6, PP2, PP3, PP4
Labcorp Genetics (formerly Invitae), Labcorp RCV001859347 SCV002243014 pathogenic Ehlers-Danlos syndrome, type 4 2021-12-18 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL3A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL3A1, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1163237). This missense change has been observed in individuals with COL3A1-related conditions (PMID: 25758994, 31600821). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 213 of the COL3A1 protein (p.Gly213Asp).
Ambry Genetics RCV002368537 SCV002657919 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-08-05 criteria provided, single submitter clinical testing The p.G213D variant (also known as c.638G>A), located in coding exon 8 of the COL3A1 gene, results from a G to A substitution at nucleotide position 638. The glycine at codon 213 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 detected in individuals reported to have Ehlers-Danlos syndrome type IV (vascular type) (Frank M et al. Eur. J. Hum. Genet., 2015 Dec;23:1657-64; Ritelli M et al. Clin. Genet., 2020 02;97:287-295). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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