Submissions for variant NM_000138.5(FBN1):c.478T>C (p.Cys160Arg)

dbSNP: rs1057518973

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415236	SCV000493043	likely pathogenic	Mitral regurgitation; Aortic dissection; Ectopia lentis	2013-12-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389968	SCV001591530	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-05-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). 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 FBN1 protein function. This variant has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 17657824, Invitae). ClinVar contains an entry for this variant (Variation ID: 374203). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 160 of the FBN1 protein (p.Cys160Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.
3billion	RCV002250623	SCV002521805	likely pathogenic	Marfan syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000374203). A different missense change at the same codon (p.Cys160Tyr) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000549250). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV002250623	SCV004123068	likely pathogenic	Marfan syndrome	2023-07-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993950	SCV004813352	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2024-02-14	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.478T>C (p.Cys160Arg) results in a non-conservative amino acid change located in an EGF-like domain (IPR000742) of the encoded protein sequence. This alters a highly conserved amino acid (HGMD) in which another pathogenic missense variant occurs (p.Cys160Tyr), suggesting this is a functionally important residue. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251380 control chromosomes (gnomAD). c.478T>C has been reported in the literature in individuals affected with Marfan Syndrome (Comeglio_2007, Franken_2017, Guo_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17657824, 28468757, 33844962). ClinVar contains an entry for this variant (Variation ID: 374203). Based on the evidence outlined above, the variant was classified as likely pathogenic.