rs727503057

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 8.15

Variant links:

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]

FBN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a disulfide_bond (size 11) in uniprot entity FBN1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000138.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ 5.0644 (greater than the threshold 3.09). Trascript score misZ 8.1787 (greater than threshold 3.09). GenCC has associacion of gene with MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.

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	Protein	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.1879C>T	p.Arg627Cys	missense_variant	16/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1 linkuse as main transcript	c.1879C>T	p.Arg627Cys	missense_variant	15/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.1879C>T	p.Arg627Cys	missense_variant	16/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

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:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727228

show subpopulations

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:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

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:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Marfan syndrome

Pathogenic:4

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). -
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	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. -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:3

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; Waldmüller 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. -
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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 23, 2019	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
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) -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.15

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.68

Sift

Benign

0.045

Sift4G

Benign

0.094

Vest4

0.87

MutPred

0.83

Gain of catalytic residue at V629 (P = 0.1096);

MVP

0.88

MPC

2.1

ClinPred

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over