Submissions for variant NM_000138.5(FBN1):c.5885A>G (p.Tyr1962Cys)

dbSNP: rs1346043320

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV003889967	SCV004704624	likely pathogenic	Marfan syndrome	2024-02-22	reviewed by expert panel	curation	The NM_00138 c.5885A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 1962 (p.Tyr1962Cys) within a calcium binding EGF-like domain of the protein (PM1). This variant was found in a proband diagnosed who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (MFS) (PMID 27112580, PP4). This variant has been reported four times in ClinVar: once as likely pathogenic and three times as uncertain significance (Variation ID: 570737). At least two other probands with clinical features of MFS carry the same variant (PMID 33483583, Invitae ClinVar, PS4_Sup). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.972, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PS4_Sup, PM2_Sup, PP2, PP3, PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691671	SCV000819459	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1962 of the FBN1 protein (p.Tyr1962Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 27112580; internal data). ClinVar contains an entry for this variant (Variation ID: 570737). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV001333240	SCV001525770	uncertain significance	Weill-Marchesani syndrome 2, dominant	2018-06-19	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002233229	SCV002511391	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2022-04-09	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.5885A>G (p.Tyr1962Cys) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) 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 (Dietz_1992). Therefore, the substitution by a cysteine may disrupt the structure of the FBN1 protein, affecting its function. Missense affecting/creating cysteine residues are one of the criteria for a causal FBN1 mutation according to the Ghent criteria for diagnosis of Marfan syndrome (Loeys_2010). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250868 control chromosomes. c.5885A>G has been reported in the literature in individuals affected with Marfan Syndrome (example, Somers_2016, Gezdirici_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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002352138	SCV002652833	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-04-15	criteria provided, single submitter	clinical testing	The p.Y1962C variant (also known as c.5885A>G), located in coding exon 47 of the FBN1 gene, results from an A to G substitution at nucleotide position 5885. The tyrosine at codon 1962 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #29 domain. 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 variant has been detected in an individual reported to have Marfan syndrome; however, details were limited (Somers AE et al. Am J Med Genet A, 2016 07;170:1786-90). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV004723080	SCV005332548	likely pathogenic	not provided	2023-11-16	criteria provided, single submitter	clinical testing	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 (PMID: 12938084, 10486319); Identified in an individual with tall stature, mitral valve prolapse, myopia, and pectus excavatum in published literature (PMID: 33483584); Not observed at significant frequency in large population cohorts (gnomAD); 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: 12938084, 10486319, 33483584)
All of Us Research Program, National Institutes of Health	RCV003889967	SCV005424739	likely pathogenic	Marfan syndrome	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 1962 of the FBN1 protein. This variant has been reported in multiple individuals with Marfan syndrome (PMID: 27112580, 33483584, 27112580, 33483583). These individual's features are highly specific for a diagnosis of Marfan syndrome. This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described. This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This gene has fewer missense variants in the general population than expected, which suggests that this gene is intolerant to missense variation. This variant is predicted to be deleterious by in silico analysis.