rs763091520

Variant names:

• chr15-48437912-G-A
• rs763091520
• NM_000138.5:c.6169C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-48437912-G-A
• chr15-48437912-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000138.5(FBN1):​c.6169C>T​(p.Arg2057*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: FBN1 NM_000138.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.554
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 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 15-48437912-G-A is Pathogenic according to our data. Variant chr15-48437912-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 200076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6169C>T	p.Arg2057*	stop_gained	Exon 51 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6169C>T	p.Arg2057*	stop_gained	Exon 50 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6169C>T	p.Arg2057*	stop_gained	Exon 51 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 16, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg2057X variant in FBN1 has been reported in 1 individual with Marfan syndrome and 1 individual with primary spontaneous pneumothorax (Liu 1997, Schrijver 2002, Zhang 2016). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 200076). This nonsense variant leads to a premature termination codon at position 2057, which is predicted to lead to a truncated or absent protein. Loss of function of the FBN1 gene is an established disease mechanism in autosomal dominant Marfan syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PVS1, PS4_Supporting, PM2. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Mar 09, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 12, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBN1 c.6169C>T (p.Arg2057X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251028 control chromosomes (gnomAD). c.6169C>T has been reported in the literature in individuals affected with Marfan Syndrome (example: Mannucci_2020 and Schrijver_2002). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Apr 02, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 18435798, 25525159, 17850668, 12068374, 27229674, 10464652, 31211624, 33648514, 32679894, 31730815, 31536524, 38225666, 34916231, 39779335) -

FBN1-related disorder Pathogenic:1

Sep 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FBN1 c.6169C>T variant is predicted to result in premature protein termination (p.Arg2057*). This variant has been reported to be causative for Marfan syndrome (Liu et al. 1997. PubMed ID: 10464652; Mannucci et al. 2019. PubMed ID: 31730815). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in FBN1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Nov 21, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg2057*) 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 individual(s) with Marfan syndrome or a related connective tissue disorder and in an individual affected with primary spontaneous pneumothorax (PMID: 10464652, 27229674). ClinVar contains an entry for this variant (Variation ID: 200076). 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	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		0.55
Vest4		0.99
GERP RS		2.0
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs763091520; hg19: chr15-48730109; COSMIC: COSV100355439;