ClinVar Genomic variation as it relates to human health

The NM_000138 c.59A>G, is a missense variant in FBN1 predicted to cause a substitution of a Tyrosine by a Cysteine at amino acid 20 (p.Tyr20Cys). This variant was found in a proband with aortic root dilatation and a systemic score of 7 or above which is a highly specific phenotype for Marfan syndrome, however, a pathogenic splice variant in FBN1 was also identified in cis in this individual (BP2). The variant segregates with the disease in 4 affected family members, who also carry the pathogenic splice variant in FBN1. The variant in FBN1 has been reported 12 times in ClinVar: 3 times as likely benign, 8 times as uncertain significance and once as likely pathogenic (Variation ID: 161245). This variant has been identified in 37 individuals of European non-Finnish origin (MAF: 0.029%) (BS1; https://gnomad.broadinstitute.org/ version 2.1.1). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of two benign arguments, PP2 cannot be used. In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple papers report as VUS; ExAC: 16/66648 Europeans; ClinVar: 1 LB, 2 VUS

Variant summary: The FBN1 c.59A>G (p.Tyr20Cys) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 41/277062 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0003 (38/126638). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in multiple affected individuals without strong evidence for causality. Although, one paper, Yang_2014 indicates the variant does segregate with disease in the family, however, clinical information is not provided for additional family members. In addition, multiple clinical diagnostic laboratories/reputable databases and publications classified this variant with conflicting classifications "uncertain significance" or "likely benign." Taken together, this variant is classified as likely benign.

Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); 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: 25812041, 25637381, 26017485, 16222657, 24941995, 29543232, 12938084)

The p.Y20C variant (also known as c.59A>G), located in coding exon 1 of the FBN1 gene, results from an A to G substitution at nucleotide position 59. The tyrosine at codon 20 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the signal peptide domain. This alteration has been reported in an individual with skeletal involvement and pneumothorax as well as individuals with abdominal and thoracic aortic aneurysms (Arbustini E et al. Hum Mutat, 2005 Nov;26:494; van de Luijtgaarden KM et al. Hum Genet, 2015 Aug;134:881-93; Weerakkody R et al. Genet Med, 2018 11;20:1414-1422). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res, 2015 Mar;25:305-15). 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 amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.