NM_000138.5(FBN1):c.5368C>T (p.Arg1790Ter) AND Marfan syndrome

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Nov 8, 2023
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:: RCV000035224.18

Allele description [Variation Report for NM_000138.5(FBN1):c.5368C>T (p.Arg1790Ter)]

NM_000138.5(FBN1):c.5368C>T (p.Arg1790Ter)

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.5368C>T (p.Arg1790Ter)

Other names:

p.R1790X:CGA>TGA

HGVS:

NC_000015.10:g.48456691G>A
NG_008805.2:g.194098C>T
NM_000138.5:c.5368C>TMANE SELECT
NP_000129.3:p.Arg1790Ter
NP_000129.3:p.Arg1790Ter
LRG_778t1:c.5368C>T
LRG_778:g.194098C>T
LRG_778p1:p.Arg1790Ter
NC_000015.9:g.48748888G>A
NM_000138.4:c.5368C>T
NM_000138.5:c.5368C>T
c.5368C>T
p.Arg1790X

Protein change:

R1790*

Links:

dbSNP: rs113249837

NCBI 1000 Genomes Browser:

rs113249837

Molecular consequence:

NM_000138.5:c.5368C>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
SCV000058869	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 5, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16222657, 16835936, 19533785, 19863550, 19618372, 25741868
SCV000781385	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]
SCV000787127	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Pathogenic (Nov 7, 2017)	germline	clinical testing
SCV001976805	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 5, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002025343	Centre of Medical Genetics, University of Antwerp	criteria provided, single submitter (Submitter's publication)	Pathogenic (Mar 1, 2021)	unknown	research	Citation Link,
SCV004827283	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 8, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 16222657, 16835936, 17627385, 17657824, 17701892, 19293843, 19533785, 19618372, 19863550, 21063442, 24793577, 26787436, 27906200, 30286810, 31730815, 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	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies.

Arbustini E, Grasso M, Ansaldi S, Malattia C, Pilotto A, Porcu E, Disabella E, Marziliano N, Pisani A, Lanzarini L, Mannarino S, Larizza D, Mosconi M, Antoniazzi E, Zoia MC, Meloni G, Magrassi L, Brega A, Bedeschi MF, Torrente I, Mari F, Tavazzi L.

Hum Mutat. 2005 Nov;26(5):494.

PubMed [citation]

PMID:: 16222657

Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes.

Sakai H, Visser R, Ikegawa S, Ito E, Numabe H, Watanabe Y, Mikami H, Kondoh T, Kitoh H, Sugiyama R, Okamoto N, Ogata T, Fodde R, Mizuno S, Takamura K, Egashira M, Sasaki N, Watanabe S, Nishimaki S, Takada F, Nagai T, Okada Y, et al.

Am J Med Genet A. 2006 Aug 15;140(16):1719-25.

PubMed [citation]

PMID:: 16835936

See all PubMed Citations (16)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000058869.6

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

Description

The p.Arg1790X variant in FBN1 has been reported in 6 individuals with clinically diagnosed Marfan Syndrome (fulfilled Ghent criteria) and 3 individuals with clinical features of Marfan-like phenotypes (Marfan syndrome suspected, but not fulfilling Ghent criteria; Arbustini 2005 PMID: 16222657, Sakai 2006 PMID: 16835936, Chung 2009 PMID: 19533785, Magyar 2009 PMID: 19618372, Yoo 2010 PMID: 19863550, Zhurayev 2016 PMID: 27724990, Stengl 2020 PMID: 33059708, Meester 2022 PMID: 35058154. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42382) and was absent from large population studies (gnomAD, v.3.1.2). This nonsense variant leads to a premature termination codon at position 1790, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FBN1 gene is an established disease mechanism of autosomal dominant Marfan syndrome. In summary, this variant meets criterion to be classified as pathogenic for autosomal dominant Marfan Syndrome. ACMG/AMP Criteria applied: PM2_supporting, PSV1, PS4_Moderate.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	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, SCV000781385.1

#	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, SCV000787127.1

#	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 Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV001976805.1

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

Description

PVS1, PM2, PP5

#	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		not provided	not provided	not provided	not provided

From Centre of Medical Genetics, University of Antwerp, SCV002025343.1

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

Description

PM2, PVS1, 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		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004827283.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (16)

Description

The c.5368C>T (p.Arg1790*) variant in of the FBN1 gene creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been identified in numerous individuals (>10) affected with clinical features of Marfan syndrome (PMID:16222657, 19618372, 16835936, 19533785, 19863550, 19293843, 17627385, 26787436). Loss of function variants are known to be pathogenic for FBN1 (PMID: 17701892, 30286810, 21063442, 17657824, 19293843). Truncating variants downstream of this variant are reported in individuals with Marfan syndrome (PMID: 27906200, 31730815, 24793577). This variant is found to be absent in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 42382). Therefore, the c.5368C>T (p.Arg1790*) variant in the FBN1 gene is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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