chr15-48520716-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.1090C>T​(p.Arg364*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

FBN1
NM_000138.5 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 3.27
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]

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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 15-48520716-G-A is Pathogenic according to our data. Variant chr15-48520716-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48520716-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FBN1NM_000138.5 linkc.1090C>T p.Arg364* stop_gained Exon 10 of 66 ENST00000316623.10 NP_000129.3 P35555
FBN1NM_001406716.1 linkc.1090C>T p.Arg364* stop_gained Exon 9 of 65 NP_001393645.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FBN1ENST00000316623.10 linkc.1090C>T p.Arg364* stop_gained Exon 10 of 66 1 NM_000138.5 ENSP00000325527.5 P35555
FBN1ENST00000559133.6 linkn.1090C>T non_coding_transcript_exon_variant Exon 10 of 67 1 ENSP00000453958.2 H0YND0
FBN1ENST00000674301.2 linkn.1090C>T non_coding_transcript_exon_variant Exon 10 of 68 ENSP00000501333.2 A0A6I8PL22
FBN1ENST00000537463.6 linkn.636+16995C>T intron_variant Intron 7 of 30 5 ENSP00000440294.2 F6U495

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Marfan syndrome Pathogenic:5
May 22, 2022
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant is shared with similarly affected mother (3billion dataset). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000199963 / PMID: 12938084). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 16, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Arg364X variant in FBN1 has been reported in at least 7 individuals with features of Marfan syndrome and segregated with disease in 2 affected individuals from 1 family (Collod-Béroud 2003, Comeglio 2007, Rand-Hendriksen 2007, Stheneur 2009, Baudhuin 2015, Tan 2017, Weerakkody 2018). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 199963). This nonsense variant leads to a premature termination codon at position 364, which is predicted to lead to a truncated or absent protein. Loss of function of the FBN1 gene is an established disease mechanism in autosomal dominant Marfan syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PVS1, PS4, PM2. -

Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Oct 08, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have rarely been reported (PMID: 27274304; 31950671). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:4
Sep 23, 2019
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PS4_moderate, PM2, PP1 -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 11, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported numerous times in association with Marfan syndrome and/or TAAD (PMID: 25652356, 12938084, 17253931, 17657824, 17663468, 19293843, 30341550, 29543232); 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: 17253931, 29543232, 34498425, 33648514, 31825148, 25525159, 17657824, 17663468, 19293843, 12938084, 25652356, 28973303, 30341550, 31211624, 33483584, 33824467, 32679894, 33059708, 27535533, 33910934, 35741789, 38094723, 37116669) -

Jun 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3
Jul 12, 2021
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 06, 2016
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R364* pathogenic mutation (also known as c.1090C>T), located in coding exon 9 of the FBN1 gene, results from a C to T substitution at nucleotide position 1090. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been previously described in multiple patients reported to have classic Marfan syndrome (Rand-Hendriksen S et al. Am J Med Genet. 2007;143A(17):1968-77; Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

-
Centre for Genomic and Experimental Medicine, University of Edinburgh
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

not specified Pathogenic:1
May 25, 2019
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The FBN1 c.1090C>T; p.Arg364Ter variant (rs794728165) is reported in the literature in multiple individuals affected with suspected Marfan syndrome (Baudhuin 2015, Collod-Beroud 2003, Comeglio 2007, Stheneur 2009, Tan 2017, Tjeldhorn 2006, Weerakkody 2018). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 199963), and is absent from general population databases (Exome Variant Server, 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 to be pathogenic. References: Baudhuin L et al. Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants. J Hum Genet. 2015 60(5):241-52. Collod-Beroud G et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 2003 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 28(9):928. 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 17(9):1121-8 Tan L et al. FBN1 mutations largely contribute to sporadic non-syndromic aortic dissection. Hum Mol Genet. 2017 Dec 15;26(24):4814-4822. Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006 10(4):258-64. Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422. -

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
Mar 11, 2020
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.1090C>T (p.Arg364X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251536 control chromosomes(gnomAD). c.1090C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (e.g. Collod-Beroud_2003, Weerakkody_2018). 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. Six ClinVar submitters (evaluation after 2014) cite the variant as 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
Nov 17, 2023
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.Arg364*) 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 individuals with Marfan syndrome (PMID: 12938084, 17657824, 17663468, 25652356). ClinVar contains an entry for this variant (Variation ID: 199963). 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
0.52
CADD
Pathogenic
35
DANN
Uncertain
1.0
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.96
D
Vest4
0.97
GERP RS
3.5

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: rs794728165; hg19: chr15-48812913; API