Submissions for variant NM_000138.5(FBN1):c.1426T>C (p.Cys476Arg)

dbSNP: rs794728326

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378778	SCV001576429	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2016-07-19	criteria provided, single submitter	clinical testing	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. 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). 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 is not present in population databases (ExAC no frequency). 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.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796184	SCV005416230	pathogenic	Marfan syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Supporting+PM5+PP2+PP3_Strong+PP4