Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001220617 | SCV001392619 | likely pathogenic | Osteogenesis imperfecta type I | 2019-06-05 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid with asparagine at codon 1413 of the COL1A1 protein (p.Asp1413Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. The observation of one or more missense substitutions at this codon (p.Asp1413Asn and p.Asp1413Glu) in affected individuals suggests that this may be a clinically significant residue (PMID: 27509835, 16786509, 26177859, 28498836). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals with osteogenesis imperfecta type 2 and type 3  (PMID: 16786509, 27509835, 29150909, 18996919). This variant is not present in population databases (ExAC no frequency). |
Prevention |
RCV003953589 | SCV004776151 | likely pathogenic | COL1A1-related condition | 2023-12-29 | criteria provided, single submitter | clinical testing | The COL1A1 c.4237G>A variant is predicted to result in the amino acid substitution p.Asp1413Asn. This variant has been reported in multiple patients with severe forms of osteogenesis imperfecta (Table S1, Bardai et al. 2016. PubMed ID: 27509835, Barnes et al. 2019. PubMed ID: 31055083, Bodian et al. 2009. PubMed ID: 18996919, Essawi et al. 2018. PubMed ID: 29150909). Functional characterization using in vitro cell lines and patient’s fibroblasts suggests that this variant is deleterious (Barnes. 2019. PubMed ID: 31055083). Another missense variant affecting this amino acid has been reported, de novo, in one patient with COL1A1-related osteogenesis imperfecta (p.Asp1413Glu, Lindahl. 2015. PubMed ID: 26177859). The c.4237G>A (p.Asp1413Asn) variant has not been reported in a large population database, indicating this variant is rare. The c.4237G>A (p.Asp1413Asn) variant is interpreted as likely pathogenic. |