Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001301326 | SCV001490492 | uncertain significance | Ehlers-Danlos syndrome, type 4 | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1436 of the COL3A1 protein (p.Ala1436Pro). This variant is present in population databases (rs148015311, 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: 1004599). 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. 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. |
Color Diagnostics, |
RCV001525421 | SCV001735514 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-05-01 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with proline at codon 1436 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 2/251334 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. |
Gene |
RCV001560494 | SCV001782920 | uncertain significance | not provided | 2021-05-12 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 1004599; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 25846194) |
CHEO Genetics Diagnostic Laboratory, |
RCV001525421 | SCV002041940 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2022-11-14 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV001525421 | SCV002632915 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2019-07-30 | criteria provided, single submitter | clinical testing | The p.A1436P variant (also known as c.4306G>C), located in coding exon 51 of the COL3A1 gene, results from a G to C substitution at nucleotide position 4306. The alanine at codon 1436 is replaced by proline, an amino acid with highly similar properties. This variant has been detected in an exome sequencing cohort, and was not reported as a primary or secondary finding; however, clinical details were limited (Sapp JC et al. Am. J. Hum. Genet., 2018 09;103:358-366). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
All of Us Research Program, |
RCV001301326 | SCV004828309 | uncertain significance | Ehlers-Danlos syndrome, type 4 | 2024-07-20 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with proline at codon 1436 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251334 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. |