NM_000138.5(FBN1):c.4621C>T (p.Arg1541Ter) AND Marfan syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 1, 2021
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:: RCV000576659.3

Allele description [Variation Report for NM_000138.5(FBN1):c.4621C>T (p.Arg1541Ter)]

NM_000138.5(FBN1):c.4621C>T (p.Arg1541Ter)

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.4621C>T (p.Arg1541Ter)

Other names:

p.R1541X:CGA>TGA

HGVS:

NC_000015.10:g.48468064G>A
NG_008805.2:g.182725C>T
NM_000138.5:c.4621C>TMANE SELECT
NP_000129.3:p.Arg1541Ter
NP_000129.3:p.Arg1541Ter
LRG_778t1:c.4621C>T
LRG_778:g.182725C>T
LRG_778p1:p.Arg1541Ter
NC_000015.9:g.48760261G>A
NM_000138.4:c.4621C>T

Protein change:

R1541*

Links:

dbSNP: rs794728228

NCBI 1000 Genomes Browser:

rs794728228

Molecular consequence:

NM_000138.5:c.4621C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000678213	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 1, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000787084	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Pathogenic (Nov 7, 2017)	germline	clinical testing
SCV002025327	Centre of Medical Genetics, University of Antwerp	criteria provided, single submitter (Submitter's publication)	Pathogenic (Mar 1, 2021)	unknown	research	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000678213

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 1, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000787084

Center for Medical Genetics Ghent, University of Ghent

no assertion criteria provided

Pathogenic
(Nov 7, 2017)

germline

clinical testing

SCV002025327

Centre of Medical Genetics, University of Antwerp

criteria provided, single submitter

(Submitter's publication)

Pathogenic
(Mar 1, 2021)

unknown

research

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV000678213.1

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

Description

FBN1 NM_000138.4 exon38 p.Arg1541* (c.4621C>T): This variant has been reported in at least 7 individuals with a clinical diagnosis or suspicion of Marfan syndrome, segregating with disease in >10 affected relatives (Halliday 1999 PMID:10647894, Loeys 2001 PMID:11700157, Halliday 2002 PMID:12161601, Matyas 2002 PMID:11933199, Behan 2003 PMID:12700307, Arbustini 2005 PMID:16222657). This variant is not present in large population studies. This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or loss of allelic expression through nonsense-mediated mRNA decay. Loss of function variants are a known mechanism of disease for this gene (Dietz, PMID: 20301510). In summary, this variant is classified as pathogenic based on the data above (several probands with variant and disease, segregation studies absence from controls, impact to protein).

#	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 Medical Genetics Ghent, University of Ghent, SCV000787084.1

#	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 Centre of Medical Genetics, University of Antwerp, SCV002025327.1

#	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

Last Updated: Sep 29, 2024

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