Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000200482 | SCV000249981 | likely pathogenic | not provided | 2014-08-20 | criteria provided, single submitter | clinical testing | TAAD is a genetically heterogeneous disorder characterized by aortic dilatation, aneurysms, dissections and/or aneurysms of other major arteries. Approximately 4% of patients with autosomal dominant Ehlers-Danlos syndrome, classic type, have been reported to have a mutation in the COL5A2 gene (Malfait F et al., 2011).p.Gly1131Ser (GGT>AGT): c.3391 G>A in exon 48 of the COL5A2 gene (NM_000393.3). A G1131S variant that is likely pathogenic was identified in the COL5A2 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G1131S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G1131S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, other mutations affecting Glycine residues (G645R, G1146A, G1149R) have been reported in association with Ehlers-Danlos syndrome. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. This variant was found in TAAD. |
| Labcorp Genetics |
RCV002229093 | SCV000631596 | uncertain significance | Ehlers-Danlos syndrome, classic type, 1 | 2021-07-31 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with serine at codon 1131 of the COL5A2 protein (p.Gly1131Ser). 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 (ExAC no frequency). This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213118). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Institute of Human Genetics, |
RCV003458353 | SCV004177257 | likely pathogenic | Ehlers-Danlos syndrome, classic type, 2 | criteria provided, single submitter | not provided |