rs1555396789

Positions:

• chr15-48463227-ACTT-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The ENST00000316623.10(FBN1):​c.5076_5078del​(p.Arg1692del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R1692R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 ENST00000316623.10 inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:7 U:2
• Conservation: PhyloP100: 8.02

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 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000316623.10
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000316623.10. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 15-48463227-ACTT-A is Pathogenic according to our data. Variant chr15-48463227-ACTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 520496.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-48463227-ACTT-A is described in Lovd as [Likely_pathogenic]. Variant chr15-48463227-ACTT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.5076_5078del	p.Arg1692del	inframe_deletion	42/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.5076_5078del	p.Arg1692del	inframe_deletion	41/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.5076_5078del	p.Arg1692del	inframe_deletion	42/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727170

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.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2023	In-frame deletion of one arginine amino acid in a non-repeat region; Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17657824, 32679894, 33844962, 27146836, 34281902, 34008892) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 03, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2024	PP4, PM2, PM4, PM6_supporting, PS4 -

Marfan syndrome Pathogenic:2 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM1, PM2, PM4, PP3 -
Pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Aug 22, 2024	NM_000138.5 c.5076_5078del is a deletion of 3 nucleotides in FBN1 predicted to cause the in-frame deletion of arginine at amino acid 1692 (p.Arg1692del) (PM4). This variant has been identified in a patient with thoracic aortic aneurysm and dissection (TAAD), ectopia lentis (EL), and a systemic score ≥ 7, which is a specific phenotype for Marfan syndrome (MFS) (PP4; University of Tokyo internal data). It has been identified in at least 5 other unrelated individuals meeting the revised Ghent criteria for a clinical diagnosis of MFS (PS4; PMIDs: 27146836, 32679894; University of Tokyo & Invitae internal data); in one of these individuals with TAAD, EL, and a systemic score of 10, a phenotype highly specific to FBN1, it was found to be inherited from an apparently mosaic and unaffected parent (PM6; Invitae internal data). This variant has also been identified in at least 4 additional unrelated individuals who do not meet clinical diagnostic criteria but have phenotypes consistent with MFS, including EL or TAAD with or without systemic features (PMIDs: 17657824, 29144511, 33844962; Bichat & Invitae internal data). In two families, the variant was found to segregate with disease in a similarly affected family member (PP1; Bichat & University of Tokyo internal data). It is present in gnomAD in 1 individual of European (non-Finnish) ancestry, with a frequency of 0.00009% (1/1111872 alleles) (PM2_supporting; https://gnomad.broadinstitute.org/, v4.0.0). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM4, PM6, PP1, PP4, PM2_supporting. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 02, 2021	- -
Uncertain significance, flagged submission	clinical testing	Ambry Genetics	Aug 30, 2019	The c.5076_5078delAAG variant (also known as p.R1692del) is located in coding exon 41 of the FBN1 gene. This variant results from an in-frame AAG deletion at nucleotide positions 5076 to 5078. This results in the in-frame deletion of an arginine at codon 1692, and is located in the TGFB#05 domain. This variant (also described as c.5074_5076delAGA) was first reported in a child with ectopia lentis and no other clinical findings of Marfan syndrome (MFS) at the time of evaluation (Comeglio P et al. Hum. Mutat., 2007 Sep;28:928). This variant has also been detected in an individual meeting clinical diagnostic criteria for MFS, as well as in his asymptomatic father (Poninska JK et al. J Transl Med, 2016 05;14:115). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2023

This variant, c.5076_5078del, results in the deletion of 1 amino acid(s) of the FBN1 protein (p.Arg1692del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Marfan syndrome (PMID: 17657824, 27146836, 32679894; Invitae). ClinVar contains an entry for this variant (Variation ID: 520496). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1555396789; hg19: chr15-48755424;