Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001983960 | SCV002279487 | uncertain significance | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2022-11-15 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 1492902). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 29499418). This variant is present in population databases (rs200331961, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 926 of the COL1A2 protein (p.Arg926His). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003479387 | SCV004223259 | benign | not specified | 2023-11-30 | criteria provided, single submitter | clinical testing | Variant summary: COL1A2 c.2777G>A (p.Arg926His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251226 control chromosomes, predominantly at a frequency of 0.00026 within the South Asian subpopulation in the gnomAD database. The observed variant frequency is approximately 52-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A2 causing Ehlers-Danlos Syndrome (5e-06), strongly suggesting that the variant is benign. c.2777G>A has been reported in the literature in one individual affected with osteogenesis imperfecta, along with a pathogenic frameshifting variant in COL1A1. c.2777G>A was found to be inherited from the unaffected mother, and COL1A1 frameshifting variant appeared to be mosaic in the unaffected father. Such co-occurrence with pathogenic variant (COL1A1 c.3178del, p.Ala1060Leufs*48) provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29499418). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. |