U.S. flag

An official website of the United States government

NM_000138.5(FBN1):c.4081T>C (p.Cys1361Arg) AND Marfan syndrome

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Dec 29, 2023
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV002246009.2

Allele description [Variation Report for NM_000138.5(FBN1):c.4081T>C (p.Cys1361Arg)]

NM_000138.5(FBN1):c.4081T>C (p.Cys1361Arg)

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.4081T>C (p.Cys1361Arg)
Other names:
NM_000138.5(FBN1):c.4081T>C; p.Cys1361Arg
HGVS:
  • NC_000015.10:g.48474534A>G
  • NG_008805.2:g.176255T>C
  • NM_000138.5:c.4081T>CMANE SELECT
  • NP_000129.3:p.Cys1361Arg
  • NP_000129.3:p.Cys1361Arg
  • LRG_778t1:c.4081T>C
  • LRG_778:g.176255T>C
  • LRG_778p1:p.Cys1361Arg
  • NC_000015.9:g.48766731A>G
  • NC_000015.9:g.48766731A>G
  • NM_000138.4:c.4081T>C
Protein change:
C1361R
Links:
dbSNP: rs1566906506
NCBI 1000 Genomes Browser:
rs1566906506
Molecular consequence:
  • NM_000138.5:c.4081T>C - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002025296Centre of Medical Genetics, University of Antwerp
criteria provided, single submitter

(Submitter's publication)		Pathogenic
(Mar 1, 2021) 		unknownresearch

Citation Link,

SCV004218516ClinGen FBN1 Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(Assertion Criteria VCEP FBN1 Version 1)		Likely pathogenic
(Dec 29, 2023) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration
not providedunknownyes22not providednot providednot providedresearch

Details of each submission

From Centre of Medical Genetics, University of Antwerp, SCV002025296.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedresearchnot provided

Description

PM2, PVS2, PP4

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided2not provided2not provided

From ClinGen FBN1 Variant Curation Expert Panel, ClinGen, SCV004218516.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

NM_000138.5 c.4081T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 1361 (p.Cys1361Arg). This variant has been identified in at least two individuals with clinical diagnoses of Marfan syndrome and in an individual with a clinical suspicion of Marfan syndrome (PP4, PS4_supporting; PMID: 35058154; CHEO internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.920). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_supporting, PP2, PP3, PP4, PM2_supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024