rs397515846

Positions:

• chr15-48427602-CAG-C

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.7167_7168delCT​(p.Cys2390fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.32

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]

FBN1 (HGNC:):

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 15-48427602-CAG-C is Pathogenic according to our data. Variant chr15-48427602-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 42420.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.7167_7168delCT	p.Cys2390fs	frameshift_variant	58/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.7167_7168delCT	p.Cys2390fs	frameshift_variant	57/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.7167_7168delCT	p.Cys2390fs	frameshift_variant	58/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Jun 15, 2023	The NM_00138 c.7165_7166, is a frameshift variant in FBN1 is predicted to result in a premature stop codon at position 2404. It is expected to cause a shift in the reading frame and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with a diagnosis of Marfan syndrome, with thoracic aortic aneurysm, skeletal features, which is a highly specific phenotype for Marfan syndrome (internal data) (PP4). This variant, also described as c.7167_7169del2 or p.Leu2389fsX16 using alternate nomenclature, has also been described in three other probands with a clinical diagnosis of Marfan syndrome (PMID 25907466, 17657824, internal data) and in three probands suspected of having Marfan syndrome (PMID 24793577, 14695540, internal data) (PS4). The variant has been identified as a de novo occurrence in an individual with a phenotype consistent with the gene but not highly specific (PM6_Supportive). This variant has been reported 5 times in ClinVar as pathogenic (Variantion ID: 42420). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/). 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: PVS1, PS4, PM6_Supportive, PM2_Supportive, PP4 -
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 for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 01, 2010	- -
Pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

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

Apr 29, 2016

Variant summary: The c.7167_7168delCT variant results in a premature termination codon, predicted to cause a truncated or absent FBN1 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.7180C>T, p.Arg2394X; c.8326C>T, p.Arg2776X). The variant is absent from the large, broad ExAC control population. The variant has been reported in multiple affected MFS patients from the literature and has been reported by multiple reputable clinical labs as "Pathogenic". Taken together, this variant has been classified as a Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 2014

The c.7167_7168delCT mutation in the FBN1 gene has been reported in one individual with Marfan or Marfan-like syndrome (reported as c.7167_7169del2 or p.Leu2389fsX16, using alternate nomenclature; Biggin et al., 2004). This individual had a positive wrist and thumb sign, joint hypermobility, highly arched palate with dental crowding, characteristic facial appearance, dilated aorta, and mitral valve prolapse. The c.7167_7168delCT mutation involves the latent transforming growth factor b1 binding protein (LTBP) domain of the FBN1 gene (Biggin et al., 2004). Additionally, c.7167_7168delCT wasnot observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This mutation causes a shift in reading frame starting at codon Cysteine 2390, changing it to a Serine, and creating a premature stop codon at position 15 of the new reading frame, denoted p.Cys2390SerfsX15. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the FBN1 gene have been reported in association with Marfan syndrome. In summary, c.7167_7168delCT in the FBN1 gene is interpreted as a disease-causing mutation. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 02, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42420). This variant is also known as c.7167_7169del2 (p.Leu2389fsX16). This premature translational stop signal has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 14695540). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys2390Serfs*15) 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). -

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: rs397515846; hg19: chr15-48719799;