Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001986009 | SCV002263445 | uncertain significance | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2023-07-07 | criteria provided, single submitter | clinical testing | 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 COL1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 1480675). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 18996919). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 234 of the COL1A2 protein (p.Arg234Cys). 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. |
| Genome Diagnostics Laboratory, |
RCV002276973 | SCV002565593 | uncertain significance | Ehlers-Danlos syndrome | 2021-12-24 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002300639 | SCV002599080 | uncertain significance | not specified | 2022-09-30 | criteria provided, single submitter | clinical testing | Variant summary: COL1A2 c.700C>T (p.Arg234Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.700C>T has been reported in the literature in at-least one individual affected with Osteogenesis imperfecta type II, however, the authors predicted the causative variant was in COL1A1 gene in this individual (example: Bodian_2009). This report does not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Ambry Genetics | RCV003303560 | SCV004000770 | uncertain significance | Cardiovascular phenotype | 2023-06-02 | criteria provided, single submitter | clinical testing | The p.R234C variant (also known as c.700C>T), located in coding exon 15 of the COL1A2 gene, results from a C to T substitution at nucleotide position 700. The arginine at codon 234 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in an osteogenesis imperfecta (OI) cohort; however, an additional alteration in COL1A1 was also identified in this case (Bodian DL et al. Hum Mol Genet, 2009 Feb;18:463-71). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |