Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000087393 | SCV003524868 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2022-02-17 | criteria provided, single submitter | clinical testing | Studies have shown that this missense change alters COL3A1 gene expression (PMID: 22038052). 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL3A1 protein function. ClinVar contains an entry for this variant (Variation ID: 101156). This variant is also known as G85V. This missense change has been observed in individuals with vascular Ehlers-Danlos syndrome (PMID: 10706896, 18043893, 22038052, 24922459, 30474650). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 252 of the COL3A1 protein (p.Gly252Val). |
| ARUP Laboratories, |
RCV003114253 | SCV003799522 | pathogenic | not provided | 2022-03-10 | criteria provided, single submitter | clinical testing | The COL3A1 c.755G>T; p.Gly252Val variant (rs587779464), also known as p.Gly85Val in traditional nomenclature, is reported in the literature in multiple individuals affected with vascular (type IV) Ehlers-Danlos syndrome (Henneton 2019, Legrand 2019, Morissette 2014, Pepin 2000). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant alters a highly conserved glycine residue in the triple helical domain, which has been shown to disrupt the formation of the collagen helix and lead to connective tissue disorders (Persikov 2004, Weerakkody 2016). Additionally, other amino acid substitutions at this codon (p.Gly252Arg, p.Gly252Asp) have been reported in an individual with EDS type IV and are considered disease-causing. Based on available information, the p.Gly252Val variant is considered to be pathogenic. References: Henneton P et al. Accuracy of Clinical Diagnostic Criteria for Patients With Vascular Ehlers-Danlos Syndrome in a Tertiary Referral Centre. Circ Genom Precis Med. 2019 Mar;12(3):e001996. PMID: 30919682. Legrand A et al. Frequency of de novo variants and parental mosaicism in vascular Ehlers-Danlos syndrome. Genet Med. 2019 Jul;21(7):1568-1575. PMID: 30474650. Morissette R et al. Transforming growth factor-ß and inflammation in vascular (type IV) Ehlers-Danlos syndrome. Circ Cardiovasc Genet. 2014 Feb;7(1):80-8. PMID: 24399159. Pepin M et al. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000 Mar 9;342(10):673-80. PMID: 10706896. Persikov A et al. Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders. Hum Mutat. 2004 Oct;24(4):330-7. PMID: 15365990. Weerakkody R et al. Targeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome. Genet Med. 2016; 18(11):1119-1127. PMID: 27011056. |
| Collagen Diagnostic Laboratory, |
RCV000087393 | SCV000120277 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |