rs397514558

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_000138.5(FBN1):​c.2920C>T​(p.Arg974Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,070 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

FBN1
NM_000138.5 missense

Scores

12
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 2.94
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

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, 0.982
PP5
Variant 15-48490013-G-A is Pathogenic according to our data. Variant chr15-48490013-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48490013-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FBN1NM_000138.5 linkuse as main transcriptc.2920C>T p.Arg974Cys missense_variant 25/66 ENST00000316623.10 NP_000129.3 P35555
FBN1NM_001406716.1 linkuse as main transcriptc.2920C>T p.Arg974Cys missense_variant 24/65 NP_001393645.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBN1ENST00000316623.10 linkuse as main transcriptc.2920C>T p.Arg974Cys missense_variant 25/661 NM_000138.5 ENSP00000325527.5 P35555

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152070
Hom.:
0
Cov.:
31
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
Cov.:
31
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152070
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74280
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/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Marfan syndrome Pathogenic:5
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2012- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Likely pathogenic, no assertion criteria providedclinical testingCenter for Medical Genetics Ghent, University of GhentNov 07, 2017- -
Pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthMar 14, 2024This missense variant replaces arginine with cysteine at codon 974 in the TGFbeta-like motif 5 of the FBN1 protein. Cysteine creating variants in TGF-beta binding domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Marfan syndrome or isolated ectopia lentis (PMID: 17627385, 17657824, 22539873, 25053872, 28941062, 34140103, 34281902, ClinVar SCV000845663.2). This variant has been shown to segregate with isolated ectopia lentis in one of the families (PMID: 22539873). 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. -
Likely pathogenic, criteria provided, single submitterclinical testingRoyal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory HubJul 27, 2017The FBN1 c.2920C>T variant has previously been reported in 9 affected members of a 5 generation family with isolated ectopia lentis (Yang et al. Mol Vis. 2012;18:945-50) and a single patient with Marfan syndrome with major skeletal, ocular and cardiovascular manifestations (Comeglio et al. Hum Mutat. 2007 ;28(9):928). It has not been detected in approximately 120,000 individuals in control populations (gnomAD database). In silico tools predict the variant will adversely affect protein structure and function and it affects a highly conserved TGFB binding domain. This variant is therefore likely to be pathogenic, but may be associated with a variable phenotype. - Other Disease Reports - This variant has been linked to other diseases: Ectopia lentis (pubmed: 22539873) - Missense Effect Predictions - 87.5% (7/8) of algorithms have predicted that this variant will adversely affect protein function -
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 16, 2023This missense variant replaces arginine with cysteine at codon 974 in the TGFbeta-like motif 5 of the FBN1 protein. Cysteine creating variants in TGF-beta binding domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Marfan syndrome or isolated ectopia lentis (PMID: 17627385, 17657824, 22539873, 25053872, 28941062, 34140103, 34281902, ClinVar SCV000845663.2). This variant has been shown to segregate with isolated ectopia lentis in one of the families (PMID: 22539873). 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 submitterclinical testingAmbry GeneticsApr 19, 2021The p.R974C pathogenic mutation (also known as c.2920C>T), located in coding exon 24 of the FBN1 gene, results from a C to T substitution at nucleotide position 2920. The arginine at codon 974 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the TGFBP#03 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues (Collod-Béroud G et al. Hum. Mut. 2003:22(3):199-208). This particular mutation has been reported in a number of Marfan syndrome (MFS) and ectopia lentis (EL) cohorts (Comeglio P et al. Hum. Mutat. 2007;28:928; Howarth R et al. Genet. Test. 2007;11:146-52; Stheneur C et al. Eur. J. Hum. Genet. 2009;17:1121-8; Li J et al. Mol. Vis. 2014;20:1017-24; Vatti L et al. Am. J. Med. Genet. A. 2017;173:2995-3002). This variant also segregated with ectopia lentis in one large Chinese family (Yang G et al. Mol. Vis. 2012;18:945-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 25, 2020The FBN1 c.2920C>T; p.Arg974Cys variant (rs397514558) is reported in the literature in several individuals affected with Marfan syndrome (Comeglio 2007, Stheneur 2009). This variant is also reported to segregate in all affected members of a large, multigenerational kindred affected with ectopia lentis (Yang 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 974 is moderately conserved, it occurs in one of the TGF-beta binding (TB) domains (Yuan 1997), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. TB domains contain eight conserved cysteine residues and the disulfide bridges formed between these residues are essential for protein folding; loss of one of these cysteines or creation of a new cysteine in this domain may interfere with proper disulfide bridge formation, disrupting protein structure (Yuan 1997). Accordingly, the revised Ghent nosology for Marfan syndrome lists missense variants creating or affecting cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 47(7): 476-85. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. Yang G et al. A novel FBN1 mutation in a Chinese family with isolated ectopia lentis. Mol Vis. 2012;18:945-50. Yuan X et al. Solution structure of the transforming growth factor beta-binding protein-like module, a domain associated with matrix fibrils. EMBO J. 1997 Nov 17;16(22):6659-66. -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 28, 2016- -
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 06, 2023Variant summary: FBN1 c.2920C>T (p.Arg974Cys) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251458 control chromosomes. c.2920C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (e.g. Comeglio_2007, Howarth_2007, Li_2014, Vatti_2017, Lopez-Sainz_2021). The variant has also been reported to cosegregate with disease in families with an Ectopia Lentis phenotype without other reported symptoms of Marfan Syndrome (Yang_2012, Chen_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight (other) submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 15, 2023This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 974 of the FBN1 protein (p.Arg974Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with isolated ectopia lentis and Marfan syndrome (PMID: 17627385, 17657824, 22539873). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39667). 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) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Ectopia lentis 1, isolated, autosomal dominant Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2012- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
33
DANN
Pathogenic
1.0
Eigen
Pathogenic
0.68
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
0.84
D
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-4.8
D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0050
D
Sift4G
Uncertain
0.0080
D
Vest4
0.87
MutPred
0.89
Loss of catalytic residue at R974 (P = 0.1585);
MVP
0.97
MPC
1.7
ClinPred
1.0
D
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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.

Other links and lift over

dbSNP: rs397514558; hg19: chr15-48782210; COSMIC: COSV104608607; API