Submissions for variant NM_000138.5(FBN1):c.1879C>T (p.Arg627Cys)

gnomAD frequency: 0.00001  dbSNP: rs727503057

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150704	SCV000198104	pathogenic	Marfan syndrome	2014-10-30	criteria provided, single submitter	clinical testing	The p.Arg627Cys variant in FBN1 has been reported in 1 individual with Ectopia L entis (Jin 2007) and 9 individuals with Marfan syndrome, including 1 individual in whom the variant occurred de novo. The variant segregated with Marfan syndrom e in 9 affected relatives from 4 families (Hayward 1994, Halliday 2002, Rommel 2 005, Waldmuller 2007, Miyazawa 2007, Stheneur 2009, Attanasio 2013). In one of t hese families, this variant was also observed in 3 asymptomatic individuals; how ever, they were not clinically evaluated for the study (Miyazawa 2007). The vari ant was absent from large population studies. In vitro functional studies provid e some evidence that this variant may impact protein function (Kirschner 2011). However, these types of assays may not accurately represent biological function. In summary, the p.Arg627Cys variant meets our criteria to be classified as path ogenic for Marfan syndrome in an autosomal dominant manner (http://www.partners. org/personalizedmedicine/LMM) based upon segregation studies, absence from contr ols, and functional evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524497	SCV000544843	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-20	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 627 of the FBN1 protein (p.Arg627Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 8004112, 12161601, 16220557, 17418587, 17679947, 23684891, 25644172). ClinVar contains an entry for this variant (Variation ID: 163480). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. Experimental studies have shown that this missense change affects FBN1 function (PMID: 15161917, 21784848). For these reasons, this variant has been classified as Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000767974	SCV000898701	pathogenic	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-11-22	criteria provided, single submitter	clinical testing	FBN1 NM_000138.4 exon 15 p.Arg627Cys (c.1879C>T): This variant has been reported in the literature in at least 10 individuals with a diagnosis, clinical suspicion or primary feature of Marfan syndrome, one of whom was reported as a de novo (Hayward 1994 PMID:8004112, Halliday 2002 PMID:12161601, Rommel 2005 PMID:16220557, Jin 2007 PMID:17679947, Miyazawa 2007 PMID:17503327, Waldmuller 2007 PMID:17418587, Stheneur 2009 PMID:19293843, Attanasio 2013 PMID:23684891, Campens 2015 PMID:25644172). This variant segregated with disease in at least 6 affected family members (Rommel 2005 PMID:16220557, Miyazawa 2007 PMID:17503327). This variant is not present in large control databases but is present in Clinvar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:163480). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies also support that this variant will impact the protein (Vollbrandt 2004 PMID:15161917, Kirschner 2011 PMID:21784848). Of note, this variant is predicted to affect a cysteine residue. Cysteine in the FBN1 gene is reported to have important functional relevance; variants that involve a cysteine residue are reported to be particularly significant (Dietz, PMID: 20301510). In summary, this variant is classified as pathogenic based on the data above (multiple probands, segregation studies, presence of a de novo, absence from controls and impact to protein).
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000150704	SCV000986692	pathogenic	Marfan syndrome	2019-08-19	criteria provided, single submitter	curation	The p.Arg627Cys is a well known missense variant reported in various individuals (PMID: 8004112, 16220557, 23684891, 12161601, 17418587, 17679947, 25644172, 20591885; DOI: 10.3760/cma.j.issn.1003-9406.2019.06.008), with a frequency of A=0.00001 (1/125568, TOPMED)(ExAC no frequency). This variant has been reported several times in ClinVar (Variation ID: 163480) with a well-established Pathogenic classification. The p.Arg627Cys substitution occurs in the cbEGF-like domain. In FBN1 gene missense affecting/creating cysteine residues is one of the criteria for pathogenic mutations (PMID: 20591885).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526942	SCV001737711	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2021-05-31	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1879C>T (p.Arg627Cys) results in a non-conservative amino acid change located in the cb EGF-like #06 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Missense affecting/creating cysteine residues and affecting the conserved residues of the EGF-consensus sequence are among the criteria considered as causal in making a diagnosis of Marfan syndrome The variant was absent in 251538 control chromosomes. c.1879C>T has been widely reported in the literature in multiple individuals affected with features of Marfan Syndrome and has subsequently been cited by others (example, Hayward_1994, Hayward_1997, Rommel_2005, Miyazawa_2007, Waldmuller_2007, Jin_2007, Halliday_2002). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in enhanced proteolytic susceptibility to a variety of proteases (example, Vollbrandt_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001556720	SCV001778351	pathogenic	not provided	2022-02-24	criteria provided, single submitter	clinical testing	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; 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).; Published functional studies demonstrate a damaging effect as fibrillin protein harboring p.(R627C) is more susceptible to proteolytic degradation by a variety of proteases (Vollbrandt et al., 2004; Kirschner et al., 2011); This variant is associated with the following publications: (PMID: 23684891, 27647783, 15161917, 32431097, 8004112, 17679947, 25644172, 19293843, 12161601, 17418587, 24941995, 31055806, 32209317, 33083483, 12938084, 33059708, 33576469, 21784848, 17503327, 16220557)
CeGaT Center for Human Genetics Tuebingen	RCV001556720	SCV001961509	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798467	SCV002041956	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-12-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001798467	SCV002052265	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-04-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 627 of the FBN1 protein. This variant creates a cysteine residue in a functionally important calcium-binding EGF-like motif and is expected to disrupt normal disulfide bridge formation and affect protein stability. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown this variant to increase susceptibility to proteolytic degradation (PMID: 15161917, 21784848). This variant has been reported in individuals affected with Marfan syndrome (PMID: 8004112, 16220557, 17503327, 23684891, 31055806, 32431097), suspected Marfan syndrome (PMID: 17679947), ectopia lentis (PMID: 12161601, 33576469), and thoracic aortic aneurysm and dissection (PMID: 17418587, 25644172). This variant has been shown to segregate with disease in four unrelated families (PMID: 17503327, 8004112, 16220557, 32431097). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV001798467	SCV002723265	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-04-10	criteria provided, single submitter	clinical testing	The p.R627C pathogenic mutation (also known as c.1879C>T), located in coding exon 15 of the FBN1 gene, results from a C to T substitution at nucleotide position 1879. The arginine at codon 627 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like #06 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 mutation has been detected in multiple unrelated patients with Marfan syndrome (MFS), MFS-related features, or ectopia lentis and was also reported to occur de novo in one individual with MFS (Hayward C et al. Hum Mol Genet. 1994;3(2):373-5; Halliday DJ et al. J Med Genet. 2002;39(8):589-93; Rommel K et al. Hum Mutat. 2005;26(6):529-39; Jin C et al. Mol Vis. 2007;13:1280-4; Waldm&uuml;ller S et al. Eur J Cardiothorac Surg. 2007;31(6):970-5; Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8; Campens L et al. Orphanet J Rare Dis. 2015;10:9). This alteration segregated with disease in one family with MFS, although some carrier individuals appeared asymptomatic (Miyazawa H et al. Am J Hum Genet. 2007;80(6):1090-102). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Illumina Laboratory Services, Illumina	RCV000150704	SCV004101371	pathogenic	Marfan syndrome	2023-07-19	criteria provided, single submitter	clinical testing	The FBN1 c.1879C>T (p.Arg627Cys) missense variant has been observed in individuals with a phenotype consistent with Marfan syndrome and has been shown to segregate with disease across multiple families (PMID: 16220557; 17418587; 17503327; 17679947; 25644172; 32431097). A functional study conducted in human cell lines demonstrated that this variant impacts protein function (PMID: 21784848). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.1879C>T (p.Arg627Cys) variant is classified as pathogenic for Marfan syndrome.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001556720	SCV005197890	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000150704	SCV000786808	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing