Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002241246 | SCV001389103 | uncertain significance | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2023-08-16 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 946407). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL1A2 protein function. This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 28725987). This variant is present in population databases (rs746187799, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 777 of the COL1A2 protein (p.Arg777His). |
| Ambry Genetics | RCV002447093 | SCV002732956 | uncertain significance | Cardiovascular phenotype | 2023-08-08 | criteria provided, single submitter | clinical testing | The p.R777H variant (also known as c.2330G>A), located in coding exon 38 of the COL1A2 gene, results from a G to A substitution at nucleotide position 2330. The arginine at codon 777 is replaced by histidine, an amino acid with highly similar properties. This alteration has been described in two Chinese cohorts, having been observed in one individual with a clinical history consistent with type III/progressively deforming osteogenesis imperfecta (Liu Y et al. Osteoporos Int, 2017 10;28:2985-2995) as well as being reported as a de novo occurrence in a fetus with short femur, polyhydramnios, cardiomegaly, hydropericardium, normal karyotype and non-diagnostic chromosomal microarray (Liu J et al. Mol Genet Genomic Med, 2019 11;7:e978). This amino acid position is highly 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. |
| Ce |
RCV003883581 | SCV004701006 | uncertain significance | not provided | 2024-02-01 | criteria provided, single submitter | clinical testing |