NM_000138.5(FBN1):c.2920C>T (p.Arg974Cys) AND Marfan syndrome

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Mar 14, 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:: RCV000032871.37

Allele description [Variation Report for NM_000138.5(FBN1):c.2920C>T (p.Arg974Cys)]

NM_000138.5(FBN1):c.2920C>T (p.Arg974Cys)

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.2920C>T (p.Arg974Cys)

HGVS:

NC_000015.10:g.48490013G>A
NG_008805.2:g.160776C>T
NM_000138.5:c.2920C>TMANE SELECT
NP_000129.3:p.Arg974Cys
NP_000129.3:p.Arg974Cys
LRG_778t1:c.2920C>T
LRG_778:g.160776C>T
LRG_778p1:p.Arg974Cys
NC_000015.9:g.48782210G>A
NM_000138.4:c.2920C>T

Protein change:

R974C; ARG974CYS

Links:

OMIM: 134797.0063; dbSNP: rs397514558

NCBI 1000 Genomes Browser:

rs397514558

Molecular consequence:

NM_000138.5:c.2920C>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
SCV000056641	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2012)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17657824, 22539873
SCV000781346	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]
SCV000786902	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Likely pathogenic (Nov 7, 2017)	germline	clinical testing
SCV000845663	Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub	criteria provided, single submitter (RBHT-CGGL ClinVar Assertion Criteria)	Likely pathogenic (Jul 27, 2017)	germline	clinical testing	Citation Link,
SCV005424852	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 15161917, 16571647, 17627385, 17657824, 17701892, 22539873, 25053872, 28941062, 34140103, 34281902, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	143475	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Consequences of cysteine mutations in calcium-binding epidermal growth factor modules of fibrillin-1.

Vollbrandt T, Tiedemann K, El-Hallous E, Lin G, Brinckmann J, John H, Bätge B, Notbohm H, Reinhardt DP.

J Biol Chem. 2004 Jul 30;279(31):32924-31. Epub 2004 May 25.

PubMed [citation]

PMID:: 15161917

The molecular genetics of Marfan syndrome and related disorders.

Robinson PN, Arteaga-Solis E, Baldock C, Collod-Béroud G, Booms P, De Paepe A, Dietz HC, Guo G, Handford PA, Judge DP, Kielty CM, Loeys B, Milewicz DM, Ney A, Ramirez F, Reinhardt DP, Tiedemann K, Whiteman P, Godfrey M.

J Med Genet. 2006 Oct;43(10):769-87. Epub 2006 Mar 29. Review.

PubMed [citation]

PMID:: 16571647
PMCID:: PMC2563177

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000056641.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a 55-year-old patient with Marfan syndrome (MFS; 154700), who had major skeletal, ocular, and cardiovascular manifestations as well as minor skin involvement, Comeglio et al. (2007) identified heterozygosity for a c.2920C-T transition in the FBN1 gene, resulting in an arg974-to-cys (R974C) substitution.

In 9 affected members of a 5-generation Chinese family with isolated ectopia lentis (ECTOL1; 129600), Yang et al. (2012) identified heterozygosity for the 2920C-T transition in exon 25 of the FBN1 gene, resulting in an R974C substitution at a highly conserved residue in the 8-cys repeat latent transforming growth factor-beta binding protein (LTBP) motif. The mutation was not found in 2 unaffected family members or in 50 ethnically matched controls.

#	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		not provided	not provided	not provided	not provided

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781346.1

#	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, SCV000786902.1

#	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 Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub, SCV000845663.2

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

Description

The FBN1 c.2920C>T variant has previously been reported in 9 affected members of a 5 generation family with isolated ectopia lentis (Yang et al. Mol Vis. 2012;18:945-50) and a single patient with Marfan syndrome with major skeletal, ocular and cardiovascular manifestations (Comeglio et al. Hum Mutat. 2007 ;28(9):928). It has not been detected in approximately 120,000 individuals in control populations (gnomAD database). In silico tools predict the variant will adversely affect protein structure and function and it affects a highly conserved TGFB binding domain. This variant is therefore likely to be pathogenic, but may be associated with a variable phenotype. - Other Disease Reports - This variant has been linked to other diseases: Ectopia lentis (pubmed: 22539873) - Missense Effect Predictions - 87.5% (7/8) of algorithms have predicted that this variant will adversely affect protein function

#	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		1	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV005424852.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (11)

Description

This missense variant replaces arginine with cysteine at codon 974 in the TGFbeta-like motif 5 of the FBN1 protein. Cysteine creating variants in TGF-beta binding domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Marfan syndrome or isolated ectopia lentis (PMID: 17627385, 17657824, 22539873, 25053872, 28941062, 34140103, 34281902, ClinVar SCV000845663.2). This variant has been shown to segregate with isolated ectopia lentis in one of the families (PMID: 22539873). 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: Dec 22, 2024

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