rs727503057

chr15-48505106-G-Achr15-48505106-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):c.1879C>T(p.Arg627Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R627H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 8.15

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 15-48505106-G-A is Pathogenic according to our data. Variant chr15-48505106-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 163480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48505106-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.1879C>T	p.Arg627Cys	missense_variant	16/66	ENST00000316623.10
FBN1	NM_001406716.1	c.1879C>T	p.Arg627Cys	missense_variant	15/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.1879C>T	p.Arg627Cys	missense_variant	16/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 19, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 30, 2014	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Aug 19, 2019	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). -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 10, 2018	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 31, 2021

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. -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

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. -

Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Nov 22, 2021

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.15	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.68
Sift	Benign	0.045	D
Sift4G	Benign	0.094	T
Vest4		0.87
MutPred		0.83		Gain of catalytic residue at V629 (P = 0.1096);
MVP		0.88
MPC		2.1
ClinPred		0.97	D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727503057; hg19: chr15-48797303; COSMIC: COSV57315655;