NM_000138.5(FBN1):c.4567C>T (p.Arg1523Ter) AND Marfan syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Apr 20, 2018
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000035205.7

Allele description [Variation Report for NM_000138.5(FBN1):c.4567C>T (p.Arg1523Ter)]

NM_000138.5(FBN1):c.4567C>T (p.Arg1523Ter)

Gene:

FBN1:fibrillin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q21.1

Genomic location:

Preferred name:

NM_000138.5(FBN1):c.4567C>T (p.Arg1523Ter)

HGVS:

NC_000015.10:g.48468427G>A
NG_008805.2:g.182362C>T
NM_000138.5:c.4567C>TMANE SELECT
NP_000129.3:p.Arg1523Ter
NP_000129.3:p.Arg1523Ter
LRG_778t1:c.4567C>T
LRG_778:g.182362C>T
LRG_778p1:p.Arg1523Ter
NC_000015.9:g.48760624G>A
NM_000138.4:c.4567C>T
c.4567C>T
p.Arg1523X

Protein change:

R1523*

Links:

dbSNP: rs397515812

NCBI 1000 Genomes Browser:

rs397515812

Molecular consequence:

NM_000138.5:c.4567C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Marfan syndrome (MFS)
Synonyms:: MARFAN SYNDROME, TYPE I; Marfan syndrome type 1; Marfan's syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007947; MedGen: C0024796; Orphanet: 284963; Orphanet: 558; OMIM: 154700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000058848	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Apr 20, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12068374, 23505274, 10874320, 19159394, 25101912, 24033266
SCV000781374	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000787077	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Pathogenic (Nov 7, 2017)	germline	clinical testing
SCV005418369	Juno Genomics, Hangzhou Juno Genomics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Premature termination mutations in FBN1: distinct effects on differential allelic expression and on protein and clinical phenotypes.

Schrijver I, Liu W, Odom R, Brenn T, Oefner P, Furthmayr H, Francke U.

Am J Hum Genet. 2002 Aug;71(2):223-37. Epub 2002 Jun 14.

PubMed [citation]

PMID:: 12068374
PMCID:: PMC379156

Marfan syndrome presenting with headache and coincidental ophthalmic artery aneurysm.

Vandersteen AM, Kenny J, Khan NL, Male A.

BMJ Case Rep. 2013 Mar 15;2013. doi: 10.1136/bcr-2012-008323.

PubMed [citation]

PMID:: 23505274
PMCID:: PMC3618733

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000058848.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Arg1523X variant in FBN1 has been reported in at least 6 individuals with clinical features of Marfan syndrome (Vandersteen 2013, Schrijver 2002, Baudhuin 2014, Soylen 2009, Youil 2000, LMM data) and has also been reported by other cl inical laboratories in ClinVar (Variation ID: 42365). It has been identified in 1/245856 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs397515812). This nonsense variant leads to a prematur e termination codon at position 1523, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FBN1 gene is an establis hed disease mechanism in individuals with Marfan syndrome. In summary, this vari ant meets criteria to be classified as pathogenic for Marfan syndrome in an auto somal dominant manner based upon presence in multiple affected individuals and t he predicted impact on the protein. ACMG/AMP Criteria applied: PVS1, PS4.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781374.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Medical Genetics Ghent, University of Ghent, SCV000787077.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Juno Genomics, Hangzhou Juno Genomics, Inc, SCV005418369.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PVS1+PM2_Supporting+PS4+PM6

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 30, 2024

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