NM_000138.5:c.4786C>T

Variant names:

• chr15-48465820-G-A
• rs113871094
• NM_000138.5:c.4786C>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.4786C>T​(p.Arg1596*) 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 2.84

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 15-48465820-G-A is Pathogenic according to our data. Variant chr15-48465820-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 36082.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
FBN1	NM_000138.5	c.4786C>T	p.Arg1596*	stop_gained	Exon 39 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.4786C>T	p.Arg1596*	stop_gained	Exon 38 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.4786C>T	p.Arg1596*	stop_gained	Exon 39 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

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

- -

Jan 13, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP2, PM2, PS2_moderate, PS4_moderate, PVS1 -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 30, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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); Identified in multiple unrelated individuals with a reported diagnosis of Marfan syndrome, or clinical manifestations of Marfan syndrome, referred for testing at GeneDx and in the published literature (Loeys et al., 2001; Maygar et al., 2009; Stheneur et al., 2009; Ogawa et al., 2011; Han et al., 2017; Zastrow et al., 2017 ); This variant is associated with the following publications: (PMID: 25525159, 21907952, 12938084, 19293843, 19618372, 28901506, 11700157, 17718856, 16756980, 15241795, 11933199, 35058154, 33282382, 31167969, 33461977, 36588568, 29768367, 28050602) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Marfan syndrome Pathogenic:4

Jan 16, 2016

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported (PMID: 11700157) and was seen once in our laboratory de novo in a 3-year-old female with dysmorphisms, developmental delay, autism, hypotonia, relative macrocephaly, failure to thrive, congenital diaphragmatic hernia, recurrent umbilical hernia, pectus carinatum, joint laxity. She also carried a de novo nonsense variant in TRPS1. -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 02, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg1596X variant has been reported in 4 individuals with clinical features o f Marfan syndrome and was shown to segregate with clinical feature in one report ed family (Loeys 2001, De Backer 2007, Magyar 2009,). In addition, this variant has been identified in one individual with clinical features of Marfan syndrome by our laboratory. This nonsense variant leads to a premature termination codon at position 1596, which is predicted to lead to a truncated or absent protein. H eterozygous loss of function of the FBN1 gene is an established disease mechanis m in Marfan syndrome. In summary, this variant meets our criteria to be classifi ed as pathogenic (http://pcpgm.partners.org/LMM). -

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PVS1, PP4 -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Dec 23, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1596* pathogenic mutation (also known as c.4786C>T), located in coding exon 38 of the FBN1 gene, results from a C to T substitution at nucleotide position 4786. This changes the amino acid from an arginine to a stop codon within coding exon 38. This variant has been detected in multiple individuals reported to have Marfan syndrome (MFS) or features consistent with MFS, and individuals from MFS cohorts (Loeys B et al. Arch Intern Med, 2001 Nov;161:2447-54; Spits C et al. Fertil Steril, 2006 Aug;86:310-20; De Backer J et al. Clin Genet, 2007 Sep;72:188-98; Magyar I et al. Hum Mutat, 2009 Sep;30:1355-64; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8Ogawa N et al. Am J Cardiol, 2011 Dec;108:1801-7; Han Q et al. Mol Med Rep, 2017 Nov;16:6620-6625; Hansen J et al. JCI Insight, 2019 Jun 4; Erhart P et al. J Thorac Dis, 2020 Nov;12:6806-6812). 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. -

Feb 22, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

Oct 07, 2024

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.4786C>T (p.Arg1596X) 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 251144 control chromosomes. c.4786C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome and has been shown to segregate with disease within families (e.g., Loeys_2001, Loeys_2004, Spits_2006, Magyar_2009, DeBacker_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11700157, 15241795, 16756980, 17718856, 19618372). ClinVar contains an entry for this variant (Variation ID: 36082). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Jan 14, 2025

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.Arg1596*) 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: 11700157, 12938084, 17718856, 19618372, 21907952, 28050602). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36082). 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

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.98
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs113871094; hg19: chr15-48758017;