NM_000138.5(FBN1):c.2722T>C (p.Cys908Arg) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 10, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000791419.9

Allele description [Variation Report for NM_000138.5(FBN1):c.2722T>C (p.Cys908Arg)]

NM_000138.5(FBN1):c.2722T>C (p.Cys908Arg)

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.2722T>C (p.Cys908Arg)

HGVS:

NC_000015.10:g.48494210A>G
NG_008805.2:g.156579T>C
NM_000138.5:c.2722T>CMANE SELECT
NP_000129.3:p.Cys908Arg
NP_000129.3:p.Cys908Arg
LRG_778t1:c.2722T>C
LRG_778:g.156579T>C
LRG_778p1:p.Cys908Arg
NC_000015.9:g.48786407A>G
NM_000138.4:c.2722T>C

Protein change:

C908R

Links:

dbSNP: rs1060501021

NCBI 1000 Genomes Browser:

rs1060501021

Molecular consequence:

NM_000138.5:c.2722T>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

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544827	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 10, 2021)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 19349279, 16571647, 17701892, 16905551, 26281765, 12203992, 24698609, 19353630, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544827

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 10, 2021)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Latent transforming growth factor beta-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites.

Ono RN, Sengle G, Charbonneau NL, Carlberg V, Bächinger HP, Sasaki T, Lee-Arteaga S, Zilberberg L, Rifkin DB, Ramirez F, Chu ML, Sakai LY.

J Biol Chem. 2009 Jun 19;284(25):16872-16881. doi: 10.1074/jbc.M809348200. Epub 2009 Apr 6.

PubMed [citation]

PMID:: 19349279
PMCID:: PMC2719323

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 (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544827.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). This variant has been reported to affect FBN1 protein function (PMID: 16905551, 26281765). This variant has been reported in several individuals affected with FBN1-related conditions (PMID: 12203992, 24698609, 19353630,¬†28941062, Invitae). Different missense variants at the same codon (p.Cys908Tyr, Cys908Gly) have also been reported in individuals with FBN1-related conditions (PMID:¬†11170092, 18471089,¬†25656438). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 908 of the FBN1 protein (p.Cys908Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: Sep 29, 2024

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