ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.547G>A (p.Gly183Ser) (rs121912926)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479050 SCV000568644 pathogenic not provided 2017-02-10 criteria provided, single submitter clinical testing The G183S pathogenic variant was identified in the COL3A1 gene. G183S, described as G16S in some publications due to alternative nomenclature, was initially reported in seven unrelated families with vascular EDS who experienced both arterial and gastrointestinal complications of the condition (Pepin et al., 2000). Furthermore, cultured fibroblasts from the probands of these families were reported to produce abnormal type III procollagen (Pepin et al., 2000). This pathogenic variant was also reported in two other unrelated individuals with a clinical diagnosis of vascular EDS (Mortani et al., 2011; Frank et al., 2015). In addition, G183S is classified as pathogenic by another clinical laboratory, and is reported to have occurred de novo in four individuals with vascular EDS (ClinVar SCV000120504.1; Landrum et al., 2016; Fokkema et al., 2011). Moreover, an abstract by D'hondt et al. (2015) reports that transgenic mice harboring the G183S variant display the clinical features of human vascular EDS, including slow wound healing and thin, translucent skin. The G183S variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The G183S variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. This substitution also affects a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL3A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Pepin et al., 2015). In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, four other variants at the same residue (G183C, G183R, G183D, G183A) have each been reported in at least one individual with vascular EDS (Smith et al., 1997; Pepin et al., 2000; Frank et al., 2015; Morissette et al., 2014), supporting the functional importance of this residue of the protein.In summary, G183S in the COL3A1 gene is interpreted as a pathogenic variant.
Invitae RCV000018768 SCV000631672 pathogenic Ehlers-Danlos syndrome, type 4 2018-05-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 183 of the COL3A1 protein (p.Gly183Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (rs121912926, ExAC no frequency). This variant has been reported in numerous individuals and families affected with Ehlers-Danlos syndrome IV (PMID: 10706896, 18043893, 24922459). This variant is also known as G16S in the literature. ClinVar contains an entry for this variant (Variation ID: 17228). 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018768 SCV000039051 pathogenic Ehlers-Danlos syndrome, type 4 2000-03-09 no assertion criteria provided literature only
Collagen Diagnostic Laboratory,University of Washington RCV000018768 SCV000120504 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing

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