ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1426T>C (p.Cys476Arg) (rs794728326)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467406 SCV000544894 likely pathogenic Marfan syndrome 2016-07-19 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 476 of the FBN1 protein (p.Cys476Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with bilateral ectopia lentis, with family history of both ectopia lentis and polycystic kidney disease. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not, as the family members were not genotyped (PMID: 21932315). This variant affects a cysteine residue located within an epidermal growth factor (EGF)-like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among individuals with Marfan syndrome (PMID: 16571647, 17701892). Indeed, a different missense substitution at this codon (p.Cys476Gly) has been reported to segregate with disease in 34 affected individuals in a large family (PMID: 7951214). In summary, this is a rare missense variant that disrupts a functionally critical cysteine residue of the FBN1 protein. The observation of a different pathogenic missense mutation at this codon further suggests that this cysteine residue is important for FBN1 protein function. Although this variant has been observed in a family with ectopia lentis and polycystic kidney disease, co-segregation of the variant with disease has not been reported. For these reasons, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000780248 SCV000917356 likely pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2018-06-04 criteria provided, single submitter clinical testing Variant summary: FBN1 c.1426T>C (p.Cys476Arg) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245946 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1426T>C, was reported in a patient that presented with bilateral ectopia lentis at 4 years old, who had a family history of poor vision on the maternal side, the mother also had symptomatic EL and a maternal family history of possible Marfan syndrome was reported (Zadeh_2011). Another variant at this location, c.1426T>G (p.Cys476Gly) has been classified as pathogenic for MFS, internally, along with HGMD reporting another variant, c.1426T>A (p.Cys476Ser). Therefore, indicating the location is a mutational hotspot. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.

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