ClinVar Miner

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

dbSNP: rs1181638652
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Total submissions: 4
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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 ( PM6 => Assumed de novo, but without confirmation of paternity and maternity (
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-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

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