Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| SIB Swiss Institute of Bioinformatics | RCV000755737 | SCV000883248 | likely pathogenic | Spondylometaphyseal dysplasia - Sutcliffe type | 2018-10-15 | criteria provided, single submitter | curation | This variant is interpreted as Likely Pathogenic, for Spondylometaphyseal dysplasia, corner fracture type, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (http://www.uniprot.org/uniprot/P02751). PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/29100092). |
| Invitae | RCV003558392 | SCV004293961 | pathogenic | not provided | 2023-12-20 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 225 of the FN1 protein (p.Cys225Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with spondylometaphyseal dysplasia corner fracture type (PMID: 29100092, 33605604). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 424645). 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 FN1 protein function with a positive predictive value of 80%. This variant disrupts the p.Cys225 amino acid residue in FN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| CHU Sainte- |
RCV000509585 | SCV000574555 | likely pathogenic | Spondylometaphyseal dysplasia | 2017-02-25 | no assertion criteria provided | research | 6 Individuals with novel FN1 mutations and spondylometaphyseal dysplasia |
| OMIM | RCV000755737 | SCV001960896 | pathogenic | Spondylometaphyseal dysplasia - Sutcliffe type | 2021-09-30 | no assertion criteria provided | literature only |