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NM_000138.5(FBN1):c.4172G>A (p.Cys1391Tyr) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 29, 2020
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:
RCV000684935.7

Allele description [Variation Report for NM_000138.5(FBN1):c.4172G>A (p.Cys1391Tyr)]

NM_000138.5(FBN1):c.4172G>A (p.Cys1391Tyr)

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.4172G>A (p.Cys1391Tyr)
HGVS:
  • NC_000015.10:g.48474293C>T
  • NG_008805.2:g.176496G>A
  • NM_000138.5:c.4172G>AMANE SELECT
  • NP_000129.3:p.Cys1391Tyr
  • NP_000129.3:p.Cys1391Tyr
  • LRG_778t1:c.4172G>A
  • LRG_778:g.176496G>A
  • LRG_778p1:p.Cys1391Tyr
  • NC_000015.9:g.48766490C>T
  • NM_000138.4:c.4172G>A
Protein change:
C1391Y
Links:
dbSNP: rs1352478541
NCBI 1000 Genomes Browser:
rs1352478541
Molecular consequence:
  • NM_000138.5:c.4172G>A - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000812398Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Feb 29, 2020)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Marfan syndrome-causing mutations in fibrillin-1 result in gross morphological alterations and highlight the structural importance of the second hybrid domain.

Mellody KT, Freeman LJ, Baldock C, Jowitt TA, Siegler V, Raynal BD, Cain SA, Wess TJ, Shuttleworth CA, Kielty CM.

J Biol Chem. 2006 Oct 20;281(42):31854-62. Epub 2006 Aug 10.

PubMed [citation]
PMID:
16905551

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
See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000812398.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

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). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys1391 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19012347), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Marfan syndrome (PMID: 27234404, 27906200, Invitae). In one of these individuals the variant was observed with another pathogenic variant in FBN1. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 1391 of the FBN1 protein (p.Cys1391Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine.

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

Last Updated: Sep 29, 2024