NM_000138.5(FBN1):c.4588C>T (p.Arg1530Cys) AND Marfan syndrome

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jul 31, 2024
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:: RCV000029740.25

Allele description [Variation Report for NM_000138.5(FBN1):c.4588C>T (p.Arg1530Cys)]

NM_000138.5(FBN1):c.4588C>T (p.Arg1530Cys)

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.4588C>T (p.Arg1530Cys)

Other names:

NM_000138.4(FBN1):c.4588C>T(p.Arg1530Cys)

HGVS:

NC_000015.10:g.48468097G>A
NG_008805.2:g.182692C>T
NM_000138.5:c.4588C>TMANE SELECT
NP_000129.3:p.Arg1530Cys
NP_000129.3:p.Arg1530Cys
LRG_778t1:c.4588C>T
LRG_778:g.182692C>T
LRG_778p1:p.Arg1530Cys
NC_000015.9:g.48760294G>A
NM_000138.4:c.4588C>T
c.4588C>T

Protein change:

R1530C

Links:

dbSNP: rs111401431

Molecular consequence:

NM_000138.5:c.4588C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000058849	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jan 17, 2008)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11700157, 17679947, 15054843, 24033266
SCV000787081	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Likely pathogenic (Nov 7, 2017)	germline	clinical testing
SCV000803472	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 31, 2018)	unknown	curation	PubMed (6) [See all records that cite these PMIDs] 19941982, 11700157, 17663468, 14695540, 17679947, 25741868
SCV002025324	Centre of Medical Genetics, University of Antwerp	criteria provided, single submitter (Submitter's publication)	Likely pathogenic (Mar 1, 2021)	unknown	research	Citation Link,
SCV002758616	Human Genetics Bochum, Ruhr University Bochum	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005424773	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 31, 2024)	germline	clinical testing	PubMed (32) [See all records that cite these PMIDs] 11700157, 14695540, 15161917, 16571647, 17253931, 17627385, 17663468, 17679947, 17701892, 19863550, 19941982, 20564469, 22772377, 24161884, 24698609, 24793577, 25652356, 25907466, 28550590, 28941062, 29198452, 29357934, 29768367, 30393980, 30838813, 31098894, 31536524, 31730815, 31825148, 36729443, 38190127, 25741868

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	unknown	yes	3	3	not provided	not provided	not provided	research
not provided	germline	unknown	1	not provided	not provided	143475	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Ectopia lentis phenotypes and the FBN1 gene.

Adès LC, Holman KJ, Brett MS, Edwards MJ, Bennetts B.

Am J Med Genet A. 2004 Apr 30;126A(3):284-9. Review.

PubMed [citation]

PMID:: 15054843

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (34)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000058849.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

#	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		1	not provided	1	not provided

From Center for Medical Genetics Ghent, University of Ghent, SCV000787081.1

#	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 SIB Swiss Institute of Bioinformatics, SCV000803472.1

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

Description

This variant is interpreted as a Likely Pathogenic, for Marfan syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:19941982). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate. Observed in several unrelated affected individuals and absent from population databases (ExAC and gnomAD) (PMID:11700157) (PMID:17663468) (PMID:14695540) (PMID:17679947) (PMID:19941982). PP3-Moderate => PP3 upgraded in strength to Moderate. Mutation creates a cystein residue. The majority of FBN1 mutations involve substitution or creation of cystein residues.

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

From Centre of Medical Genetics, University of Antwerp, SCV002025324.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	research	not provided

Description

PM2, PS1, PP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		3	not provided	3	not provided

From Human Genetics Bochum, Ruhr University Bochum, SCV002758616.1

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

Description

ACMG criteria used to clasify this variant: PP3, PS4, PM2, PM5, PP1, PP2

#	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 All of Us Research Program, National Institutes of Health, SCV005424773.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (32)

Description

This missense variant replaces arginine with cysteine at codon 1530 in a TGFbeta-like domain of the FBN1 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Cysteine creating variants in cbEGF-like and TGFbeta-like domains have been shown to affect protein stability and are overrepresented among patients with Marfan syndrome (PMID: 15161917, 16571647, 17701892). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 individuals affected with Marfan syndrome (PMID: 17663468, 19863550, 22772377, 24161884, 24793577, 25907466, 28941062, 29198452, 29357934, 30393980, 30838813, 31730815, 31825148) and in multiple individuals affected with ectopia lentis (PMID: 11700157, 14695540, 17679947, 19941982, 20564469, 24698609, 31098894, 36729443, 38190127). It has also been reported in multiple individuals suspected to be affected with Marfan syndrome (PMID: 17253931, 17627385, 25652356, 29768367, 31536524) and in one individual affected with thoracic aortic aneurysm (PMID: 28550590). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 17663468, 17679947, 19941982, 29357934, 36729443). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 20, 2026

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