chr15-48463227-ACTT-A

Variant names:

• chr15-48463227-ACTT-A
• rs1555396789
• NM_000138.5:c.5076_5078delAAG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000138.5(FBN1):​c.5076_5078delAAG​(p.Arg1692del) variant causes a disruptive 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 (★★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 disruptive_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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000138.5. 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 rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.5076_5078delAAG	p.Arg1692del	disruptive_inframe_deletion	Exon 42 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.5076_5078delAAG	p.Arg1692del	disruptive_inframe_deletion	Exon 41 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.5076_5078delAAG	p.Arg1692del	disruptive_inframe_deletion	Exon 42 of 66	1	NM_000138.5	ENSP00000325527.5

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

Dec 15, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jul 03, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM2, PM4, PM6_supporting, PS4 -

Marfan syndrome Pathogenic:2 Uncertain:1

Aug 22, 2024

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PM4, PP3 -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

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

Aug 30, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

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. -

Jul 02, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). 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;