Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001233702 | SCV001406308 | uncertain significance | Ehlers-Danlos syndrome, type 4 | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1091 of the COL3A1 protein (p.Arg1091Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 960219). 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 not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. 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. |
| Fulgent Genetics, |
RCV002497798 | SCV002790077 | uncertain significance | Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome | 2021-11-17 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV003528280 | SCV004363023 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2022-12-13 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with serine at codon 1091 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has been identified in 1/250370 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Molecular Genetics, |
RCV003994240 | SCV004812494 | uncertain significance | Ehlers-Danlos syndrome, dominant type 4 | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change in COL3A1 is predicted to replace arginine with serine at codon 1091, p.(Arg1091Ser). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the triple helical domain. There is a large physicochemical difference between arginine and serine. This variant is present in a single European (non-Finnish) individual in gnomAD v2.1 (1/113,190 alleles). To our knowledge, this variant has not been reported in the literature in any individuals with COL3A1-related disease. It was has been reported as a variant of uncertain significance (ClinVar ID: 960219). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting. |
| All of Us Research Program, |
RCV001233702 | SCV004836362 | uncertain significance | Ehlers-Danlos syndrome, type 4 | 2024-01-11 | criteria provided, single submitter | clinical testing |