rs794728228

Positions:

• chr15-48468064-G-A

Variant summary

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

The ENST00000316623.10(FBN1):​c.4621C>T​(p.Arg1541Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,852 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: 0.0000014 (0 hom.)
• Consequence: FBN1 ENST00000316623.10 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.79

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 15-48468064-G-A is Pathogenic according to our data. Variant chr15-48468064-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 200052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48468064-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.4621C>T	p.Arg1541Ter	stop_gained	38/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.4621C>T	p.Arg1541Ter	stop_gained	37/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.4621C>T	p.Arg1541Ter	stop_gained	38/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

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: 0.00000180

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:3

Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 01, 2017	FBN1 NM_000138.4 exon38 p.Arg1541* (c.4621C>T): This variant has been reported in at least 7 individuals with a clinical diagnosis or suspicion of Marfan syndrome, segregating with disease in >10 affected relatives (Halliday 1999 PMID:10647894, Loeys 2001 PMID:11700157, Halliday 2002 PMID:12161601, Matyas 2002 PMID:11933199, Behan 2003 PMID:12700307, Arbustini 2005 PMID:16222657). This variant is not present in large population studies. This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or loss of allelic expression through nonsense-mediated mRNA decay. Loss of function variants are a known mechanism of disease for this gene (Dietz, PMID: 20301510). In summary, this variant is classified as pathogenic based on the data above (several probands with variant and disease, segregation studies absence from controls, impact to protein). -
Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PVS1, PP4 -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 13, 2016	The p.R1541* pathogenic mutation (also known as c.4621C>T), located in coding exon 37 of the FBN1 gene, results from a C to T substitution at nucleotide position 4621. This changes the amino acid from an arginine to a stop codon within coding exon 37. This alteration has been found to result in reduced levels of fibrillin-1 (Halliday D et al. Hum. Genet., 1999 Dec;105:587-97). Multiple studies have identified the alteration in patients with a diagnosis of Marfan syndrome or Marfan-related symptoms (Loeys B et al. Arch. Intern. Med., 2001 Nov;161:2447-54; Arbustini E et al. Hum. Mutat., 2005 Nov;26:494; Behan WM et al. J. Neurol. Neurosurg. Psychiatr., 2003 May;74:633-8). 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:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 14, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2022	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: 11933199, 19012347, 12915484, 31536524, 30341550, 31098894, 25525159, 16220557, 18435798, 19618372, 21542060, 11700157, 12068374, 22913777, 17657824, 10647894, 23684891, 16222657, 12161601, 12700307, 25101912, 28973303, 34921932) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 20, 2017

Variant summary: The FBN1 c.4621C>T (p.Arg1541X) variant results in a premature termination codon, predicted to cause a truncated or absent FBN1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121346 control chromosomes and has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change creates a premature translational stop signal (p.Arg1541*) 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: 10647894, 11933199, 12161601, 12700307, 16222657, 17657824, 23684891). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200052). 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	44
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.97
GERP RS		3.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs794728228; hg19: chr15-48760261;