Submissions for variant NM_212482.4(FN1):c.367T>C (p.Cys123Arg)

dbSNP: rs1553667072

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000575065	SCV000883266	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: PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/29100092). 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. Replaces a cysteine involved in disulfid (http://www.uniprot.org/uniprot/P02751).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526994	SCV003524898	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 424644). This missense change has been observed in individual(s) with spondylometaphyseal dysplasia, 'corner fracture' type (PMID: 29100092). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 123 of the FN1 protein (p.Cys123Arg).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000575065	SCV005399682	pathogenic	Spondylometaphyseal dysplasia - Sutcliffe type	2024-10-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. This gene has previously been reported in association with haploinsufficiency, however, dominant negative appears to be the likely mechanism of disease (PMID: 29100092, Dinesh. N. et al. 2023).(I) 0107 - This gene is associated with autosomal dominant disease. Variants associated with glomerulopathy with fibronectin deposits 2 (MIM#601894) lie within the C-terminus, while variants associated with spondylometaphyseal dysplasia, corner fracture type (MIM#184255) lie within the N-terminus (domains I-1 to I-5) and often affect the cysteine residues involved in disulphide bonds (PMIDs: 29100092, 32200603). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been observed (PMID: 32200603). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated fibronectin type I domain and affects a cysteine residue involved in a disulphide bond (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Cys123Tyr) has a single de novo report in an individual with spondylometaphyseal dysplasia, corner fracture type (PMID: 30599297). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has multiple unrelated reports in affected individuals, two of which are de novo (ClinVar, DECIPHER, PMID: 29100092). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CHU Sainte-Justine Research Center, University of Montreal	RCV000509582	SCV000574554	likely pathogenic	Spondylometaphyseal dysplasia	2017-02-25	no assertion criteria provided	research	6 Individuals with novel FN1 mutations and spondylometaphyseal dysplasia
OMIM	RCV000575065	SCV000676923	pathogenic	Spondylometaphyseal dysplasia - Sutcliffe type	2017-12-28	no assertion criteria provided	literature only