chr15-48432947-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000138.5(FBN1):​c.6658C>T​(p.Arg2220*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,324 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN1
NM_000138.5 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 10.0
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 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-48432947-G-A is Pathogenic according to our data. Variant chr15-48432947-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN1NM_000138.5 linkc.6658C>T p.Arg2220* stop_gained Exon 55 of 66 ENST00000316623.10 NP_000129.3 P35555
FBN1NM_001406716.1 linkc.6658C>T p.Arg2220* stop_gained Exon 54 of 65 NP_001393645.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN1ENST00000316623.10 linkc.6658C>T p.Arg2220* stop_gained Exon 55 of 66 1 NM_000138.5 ENSP00000325527.5 P35555

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461324
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726982
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Marfan syndrome Pathogenic:5
Apr 18, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The Arg2220X variant (FBN1) has been reported in two Japanese probands with clin ical features of Marfan syndrome and was absent in 100 control chromosomes from healthy Japanese individuals (Matsukawa 2001, Ogawa 2011). In addition, this var iant has been identified in 1/1090 chromosomes from a broad, though clinically a nd racially unspecified population (dbSNP rs113001196). This nonsense variant le ads to a premature termination codon at position 2220, which is predicted to lea d to a truncated or absent protein. Loss of function in the FBN1 gene is an est ablished disease mechanism in Marfan patients. In summary, this variant is likel y to be pathogenic, though segregation studies and functional analyses are requi red to fully establish the pathogenicity of this variant. The clinical significa nce of this sequence variant should be interpreted in the context of this indivi dual's clinical manifestation. -

Nov 07, 2017
Center for Medical Genetics Ghent, University of Ghent
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 21, 2020
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

A heterozygous nonsense variant was identified, NM_000138.4(FBN1):c.6658C>T in exon 55 of 66 of the FBN1 gene. This nonsense variant is predicted to create a change of arginine to a stop at amino acid position 2220 of the protein, NP_000129.3(FBN1):p.(Arg2220*), resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is not present in the gnomAD population database. It has been previously reported in patients with Marfan syndrome (ClinVar; Becerra-Munoz, V.M. et al., 2018). Other variants predicted to cause NMD have been reported as pathogenic in individuals with this condition (ClinVar). Subsequent analysis of parental samples indicated this variant to be de novo. Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Mar 01, 2021
Centre of Medical Genetics, University of Antwerp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PM2, PVS1, PP4 -

Jan 26, 2023
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Pathogenic:1
Aug 10, 2018
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The FBN1 c.6658C>T; p.Arg2220Ter variant (rs113001196) has been described in several individuals affected with Marfan syndrome (Attanasio 2013, Collod-Beroud 2003, Comeglio 2007, Matsukawa 2001, Ogawa 2011, Wang 2013). It is reported as pathogenic in ClinVar (Variation ID: 42407), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. Pathogenic FBN1 variants are most commonly causative for Marfan syndrome (MFS); clinical manifestations are variable. Additionally, other phenotypes including neonatal Marfan syndrome, mitral valve prolapse syndrome, MASS syndrome, thoracic aortic aneurysms and aortic dissections (TAAD), Shprintzen-Goldberg syndrome, Weill-Marchesani syndrome as well as autosomal dominant ectopia lentis are also associated with FBN1 pathogenic variants. Offspring of this individual have a 50 percent chance of inheriting the causative variant. References: Attanasio M et al. Dural ectasia and FBN1 mutation screening of 40 patients with Marfan syndrome and related disorders: role of dural ectasia for the diagnosis. Eur J Med Genet. 2013 Jul;56(7):356-60. Collod-Beroud G et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 2003 Sep;22(3):199-208. 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. Matsukawa R et al. Eight novel mutations of the FBN1 gene found in Japanese patients with Marfan syndrome. Hum Mutat. 2001;17(1):71-2. Ogawa N et al. Evaluating Japanese patients with the Marfan syndrome using high-throughput microarray-based mutational analysis of fibrillin-1 gene. Am J Cardiol. 2011 Dec 15;108(12):1801-7. Wang WJ et al. Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections. J Mol Med (Berl). 2013 Jan;91(1):37-47. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Dec 01, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R2220* pathogenic mutation (also known as c.6658C>T), located in coding exon 54 of the FBN1 gene, results from a C to T substitution at nucleotide position 6658. This changes the amino acid from an arginine to a stop codon within coding exon 54. This alteration has been reported in cohorts of subjects with FBN1-related disease (Matsukawa R et al. Hum Mutat, 2001;17:71-2; Comeglio P et al. Hum Mutat, 2007 Sep;28:928; Somers AE et al. Am J Med Genet A, 2016 Jul;170:1786-90; Becerra-Muñoz VM et al. Orphanet J Rare Dis, 2018 Jan;13:16; Meester JAN et al. Genet Med, 2022 May;24:1045-1053). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Isolated thoracic aortic aneurysm Pathogenic:1
Sep 01, 2018
Department of Vascular Biology, Beijing Anzhen Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
May 13, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: FBN1 c.6658C>T (p.Arg2220X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250986 control chromosomes (gnomAD). c.6658C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (Attanasio_2013, Becerra-Munoz_2018, Comeglio_2007, Franken_2016, Matsukawa_2001). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1
Apr 27, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Identified in a patient with isolated TAAD (iTAAD) in published literature (Li et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 21907952, 17657824, 12938084, 23684891, 22772377, 27112580, 29357934, 26787436, 11139245, 27535533, 35058154, 33824467) -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Dec 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg2220*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Marfan syndrome (PMID: 11139245, 17657824, 22772377, 23684891, 27112580, 29357934). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 42407). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
46
DANN
Uncertain
1.0
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Uncertain
0.93
D
Vest4
0.98
GERP RS
5.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs113001196; hg19: chr15-48725144; API