Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV001772957 | SCV002003650 | uncertain significance | not provided | 2021-04-02 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (Stenson et al., 2014) |
| Labcorp Genetics |
RCV001868629 | SCV002298263 | uncertain significance | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2023-08-04 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1007 of the COL1A2 protein (p.Asp1007Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with COL1A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1314448). 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 COL1A2 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. |
| Neuberg Centre For Genomic Medicine, |
RCV003339738 | SCV004047139 | uncertain significance | Osteogenesis imperfecta, perinatal lethal | criteria provided, single submitter | clinical testing | The missense variant c.3019G>A (p.Asp1007Asn) in COL1A2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Uncertain Significance. The p.Asp1007Asn variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.002598% is reported in gnomAD. The amino acid Asp at position 1007 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance. | |
| Pittsburgh Clinical Genomics Laboratory, |
RCV004783979 | SCV005397236 | uncertain significance | Ehlers-danlos syndrome, arthrochalasia type, 2 | 2022-07-07 | criteria provided, single submitter | clinical testing | This sequence variant is a single nucleotide substitution (G>A) at coding position 3019 of the COL1A2 gene that results in an aspartic acid to asparagine amino acid change at residue 1007 of the COL1A2 protein. This variant is found within a collagen triple helix repeat domain and alters the X residue of one of the Gly-X-Y repeats, where X and Y are variable amino acids. This is a previously reported variant (ClinVar) that has not been observed in the published literature in individuals with COL1A2-related disease, to our knowledge. This variant is present in control population datasets (gnomAD database 6 of 230940 alleles or 0.0026%). Multiple bioinformatic tools queried predict that this variant would be damaging, and the Asp1007 residue is highly conserved across the mammalian species examined. Studies testing the effect of this variant on protein function have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: PM2, PP2, PP3 |