rs113249837

chr15-48456691-G-A

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.5368C>T(p.Arg1790Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,698 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 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -0.372

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 15-48456691-G-A is Pathogenic according to our data. Variant chr15-48456691-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.5368C>T	p.Arg1790Ter	stop_gained	44/66	ENST00000316623.10
FBN1	NM_001406716.1	c.5368C>T	p.Arg1790Ter	stop_gained	43/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.5368C>T	p.Arg1790Ter	stop_gained	44/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461698 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727162

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 08, 2023	The c.5368C>T (p.Arg1790*) variant in of the FBN1 gene creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been identified in numerous individuals (>10) affected with clinical features of Marfan syndrome (PMID:16222657, 19618372, 16835936, 19533785, 19863550, 19293843, 17627385, 26787436). Loss of function variants are known to be pathogenic for FBN1 (PMID: 17701892, 30286810, 21063442, 17657824, 19293843). Truncating variants downstream of this variant are reported in individuals with Marfan syndrome (PMID: 27906200, 31730815, 24793577). This variant is found to be absent in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 42382). Therefore, the c.5368C>T (p.Arg1790*) variant in the FBN1 gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PVS1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 05, 2021	PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 05, 2023	The p.Arg1790X variant in FBN1 has been reported in 6 individuals with clinically diagnosed Marfan Syndrome (fulfilled Ghent criteria) and 3 individuals with clinical features of Marfan-like phenotypes (Marfan syndrome suspected, but not fulfilling Ghent criteria; Arbustini 2005 PMID: 16222657, Sakai 2006 PMID: 16835936, Chung 2009 PMID: 19533785, Magyar 2009 PMID: 19618372, Yoo 2010 PMID: 19863550, Zhurayev 2016 PMID: 27724990, Stengl 2020 PMID: 33059708, Meester 2022 PMID: 35058154. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42382) and was absent from large population studies (gnomAD, v.3.1.2). This nonsense variant leads to a premature termination codon at position 1790, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FBN1 gene is an established disease mechanism of autosomal dominant Marfan syndrome. In summary, this variant meets criterion to be classified as pathogenic for autosomal dominant Marfan Syndrome. ACMG/AMP Criteria applied: PM2_supporting, PSV1, PS4_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2022

The p.R1790* pathogenic mutation (also known as c.5368C>T), located in coding exon 43 of the FBN1 gene, results from a C to T substitution at nucleotide position 5368. This alteration changes the amino acid from an arginine to a stop codon within coding exon 43. This mutation has been reported in numerous Marfan syndrome cohorts (e.g., Arbustini E et al. Hum Mutat. 2005;26(5):494; Magyar I et al. Hum. Mutat. 2009;30:1355-64; Stheneur C et al. Eur. J. Hum. Genet. 2009;17:1121-8; Franken R et al. Eur. Heart J, 2016;37:3285-3290). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 01, 2022

Has been reported several times in association with Marfan syndrome or other Marfan-like syndrome in unrelated patients referred for genetic testing at GeneDx and in the published literature (Arbustini et al., 2005; Sakai et al., 2006; Howarth et al., 2007; Chung et al., 2009; Magyar et al., 2009; Yoo et al., 2010; Stengl et al., 2020); 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: 16222657, 19533785, 16835936, 17627385, 19293843, 26787436, 19863550, 19618372, 33059708) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 27, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1790*) 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 premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 16222657, 16835936, 19533785, 19618372, 19863550, 26787436). ClinVar contains an entry for this variant (Variation ID: 42382). 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	0.56
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Uncertain	0.22
Eigen_PC	Benign	-0.035
FATHMM_MKL	Benign	0.70	D
MutationTaster	Benign	1.0	A
Vest4		1.0
GERP RS		-4.1

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

Other links and lift over

dbSNP: rs113249837; hg19: chr15-48748888; COSMIC: COSV57331018;