Submissions for variant NM_000138.5(FBN1):c.6448C>T (p.Arg2150Cys)

gnomAD frequency: 0.00001  dbSNP: rs76702162

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589021	SCV000233870	likely pathogenic	not provided	2023-05-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Identified independently and in conjunction with additional cardiogenetic variants in individuals referred for TAAD, Marfan syndrome, and related disorders at GeneDx, but segregation data is limited or absent at this time; Introduces a new cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1- related disorders (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 19161152, 33059708, 31730815, 12938084)
Ambry Genetics	RCV003243004	SCV000319256	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-05-08	criteria provided, single submitter	clinical testing	The p.R2150C variant (also known as c.6448C>T), located in coding exon 52 of the FBN1 gene in the cb EGF-like #32 domain, results from a C to T substitution at nucleotide position 6448. The arginine at codon 2150 is replaced by cysteine, an amino acid with highly dissimilar properties. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This alteration has been observed in individuals with clinical features of Marfan syndrome (Turner CL et al. Am J Med Genet A, 2009 Feb;149A:161-70, Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV001306630	SCV001496011	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2150 of the FBN1 protein (p.Arg2150Cys). This variant is present in population databases (rs76702162, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 19161152, 31730815; Invitae). ClinVar contains an entry for this variant (Variation ID: 200084). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg2150 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 28973303, 31098894; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003243004	SCV004240584	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-08-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589021	SCV000695582	uncertain significance	not provided	2016-11-21	flagged submission	clinical testing	Variant summary: The FBN1 c.6448C>T (p.Arg2150Cys) causes a missense change involving a conserved nucleotide located in a EGF-like domain, which 4/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "damaging" outcome, although these predictions have yet to be functionally assessed. The variant alters an Arginine to Cysteine. Cysteines are vital for proper FBN1 function and alterations, although this variant creates another Cysteine instead of eliminating a Cysteine, it could lead to disruption of disulfide binding, secondary or tertiary structure, or possibly impairing fibrillin interactions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121088 (1/60544), which does not exceed the estimated maximal expected allele frequency for a pathogenic FBN1 variant of 1/8888. The variant of interest has been reported in one affected individual via a publication that does not fulfill the Ghent criteria. In addition, the variant of interest has been cited by multiple clinical diagnostic laboratories/databases with a classification of "uncertain significance." Therefore, due to the nature of this variant, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Pathogenic," until additional information becomes available.