ClinVar Miner

Submissions for variant NM_212482.4(FN1):c.2918A>G (p.Tyr973Cys)

dbSNP: rs137854488
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000017722 SCV001427189 pathogenic Glomerulopathy with fibronectin deposits 2 2019-02-10 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_212482.3(FN1):c.2918A>G, has been identified in exon 19 of 46 of the FN1 gene (NB: This variant is non-coding in alternative transcripts). The variant is predicted to result in a major amino acid change from tyrosine to cysteine at position 973 of the protein (NP_997647.1(FN1):p.(Tyr973Cys)). The tyrosine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the Hep III heparin-binding domain (Castelletti, F., et al. (2008)) and fibronectin type III functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in the gnomAD population database. The variant has been previously described as pathogenic and segregated with disease in multiple families with glomerulopathy with fibronectin deposits (ClinVar, Ohtsubo, H., et al. (2016), Ertoy Baydar, D., et al. (2013)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Fulgent Genetics, Fulgent Genetics RCV002482881 SCV002779341 pathogenic Glomerulopathy with fibronectin deposits 2; Spondylometaphyseal dysplasia - Sutcliffe type 2024-02-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV005089267 SCV005834178 pathogenic not provided 2024-10-31 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 973 of the FN1 protein (p.Tyr973Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with glomerulopathy with fibronectin deposits (PMID: 18268355, 32939031). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16325). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000017722 SCV000037999 pathogenic Glomerulopathy with fibronectin deposits 2 2008-02-19 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV004745163 SCV005359912 pathogenic FN1-related disorder 2024-05-29 no assertion criteria provided clinical testing The FN1 c.2918A>G variant is predicted to result in the amino acid substitution p.Tyr973Cys. This variant has been reported in multiple individuals with glomerulopathy with fibronectin deposits and segregated with the disease in at least one family (see for example, Castelletti et al 2008. PubMed ID: 18268355; Jayasinghe et al 2020. PubMed ID: 32939031). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

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