rs727505006

Variant names:

• chr15-48487402-G-A
• rs727505006
• NM_000138.5:c.3373C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000138.5(FBN1):​c.3373C>T​(p.Arg1125*) variant causes a stop gained change. 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.19

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 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 15-48487402-G-A is Pathogenic according to our data. Variant chr15-48487402-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48487402-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3373C>T	p.Arg1125*	stop_gained	Exon 28 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3373C>T	p.Arg1125*	stop_gained	Exon 27 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3373C>T	p.Arg1125*	stop_gained	Exon 28 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:4

Mar 06, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg1125X variant in FBN1 has been reported in six individuals with clinical features of Marfan syndrome (Attanasio 2008, Comeglio 2007, Hung 2009, Rommel 20 05, Stheneur 2009, Sheikhzadeh 2012). This nonsense variant leads to a premature termination codon at position 1125, which is predicted to lead to a truncated o r absent protein. Heterozygous loss of function of the FBN1 gene is an establish ed disease mechanism in Marfan syndrome. In summary, this variant meets our crit eria to be classified as pathogenic (http://pcpgm.partners.org/LMM). The presenc e of a heterozygous pathogenic variant in FBN1 is consistent with a diagnosis of Marfan syndrome, but this information should be reconciled with the complete cl inical history of this individual. -

Nov 26, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PVS1, PP4 -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Nov 15, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1125* pathogenic mutation (also known as c.3373C>T), located in coding exon 27 of the FBN1 gene, results from a C to T substitution at nucleotide position 3373. This changes the amino acid from an arginine to a stop codon within coding exon 27. This variant has been detected in multiple unrelated individuals with Marfan syndrome (MFS), or features consistent with a diagnoses of MFS (Comeglio P et al. Hum Mutat, 2007 Sep;28:928; Attanasio M et al. Clin Genet, 2008 Jul;74:39-46; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Hung CC et al. Ann Hum Genet, 2009 Nov;73:559-67; Sheikhzadeh S et al. Clin Genet, 2012 Sep;82:240-7; Becerra-Muñoz VM et al. Orphanet J Rare Dis, 2018 Jan;13:16; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164; Li Y et al. Am J Transl Res, 2021 May;13:4281-4295; 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). 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. -

Mar 30, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jul 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBN1 c.3373C>T; p.Arg1125Ter variant (rs727505006) is reported in the literature in individuals with clinical features of Marfan syndrome (Becerra-Munoz 2018, Mannucci 2020, Overwater 2018, Rommel 2005, Weerakkody 2016), and is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 179632). This variant is absent from the 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: Becerra-Munoz VM et al. The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. Orphanet J Rare Dis. 2018 Jan 22;13(1):16. PMID: 29357934. Mannucci L et al. Mutation analysis of the FBN1 gene in a cohort of patients with Marfan Syndrome: A 10-year single center experience. Clin Chim Acta. 2020 Feb;501:154-164. PMID: 31730815. Overwater E et al. Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. Hum Mutat. 2018 Sep;39(9):1173-1192. PMID: 29907982. Rommel K et al. Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome. Hum Mutat. 2005 Dec;26(6):529-39. PMID: 16220557. Weerakkody RA et al. Targeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome. Genet Med. 2016 Nov;18(11):1119-1127. PMID: 27011056. -

Jul 09, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple patients with clinical features of Marfan syndrome in published literature and found to segregate with disease in at least one family (PMID: 18435798, 16220557, 17657824, 19839986, 19293843, 21883168, 29357934); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21883168, 24941995, 31730815, 25525159, 16220557, 19012347, 19293843, 19618372, 27011056, 19839986, 17657824, 29907982, 29357934, 31536524, 35058154, 34150014, 23684891, 35972748, 36945115, 18435798) -

FBN1-related disorder Pathogenic:1

Jun 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FBN1 c.3373C>T variant is predicted to result in premature protein termination (p.Arg1125*). This variant has been reported in numerous individuals with Marfan syndrome (see for example, Rommel et al. 2005. PubMed ID: 16220557; Hung et al. 2009. PubMed ID: 19839986; Mannucci et al. 2019. PubMed ID: 31730815). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in FBN1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Sep 11, 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.Arg1125*) 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: 16220557, 19839986, 23684891, 27011056, 29357934, 29907982). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179632). 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	0.62
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.94
GERP RS		4.7

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

Other links and lift over

dbSNP: rs727505006; hg19: chr15-48779599;