Submissions for variant NM_212482.4(FN1):c.675C>G (p.Cys225Trp)

dbSNP: rs1181638652

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).
Labcorp Genetics (formerly Invitae), Labcorp	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-Justine Research Center, University of Montreal	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