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NM_000138.5(FBN1):c.8015G>A (p.Cys2672Tyr) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Apr 28, 2023
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:
RCV003767940.2

Allele description [Variation Report for NM_000138.5(FBN1):c.8015G>A (p.Cys2672Tyr)]

NM_000138.5(FBN1):c.8015G>A (p.Cys2672Tyr)

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.8015G>A (p.Cys2672Tyr)
HGVS:
  • NC_000015.10:g.48415572C>T
  • NG_008805.2:g.235217G>A
  • NM_000138.5:c.8015G>AMANE SELECT
  • NP_000129.3:p.Cys2672Tyr
  • NP_000129.3:p.Cys2672Tyr
  • LRG_778t1:c.8015G>A
  • LRG_778:g.235217G>A
  • LRG_778p1:p.Cys2672Tyr
  • NC_000015.9:g.48707769C>T
  • NM_000138.4:c.8015G>A
Protein change:
C2672Y
Links:
dbSNP: rs1555393831
NCBI 1000 Genomes Browser:
rs1555393831
Molecular consequence:
  • NM_000138.5:c.8015G>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
SCV004570915Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Apr 28, 2023)
germlineclinical testing

PubMed (7)
[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

Novel FBN1 mutation in a family with inherited Marfan Syndrome: p.Cys2672Arg.

Cetinkaya A, Karaman A, Mutlu MB, Yavuz T.

Congenit Anom (Kyoto). 2018 Jan;58(1):41-43. doi: 10.1111/cga.12220. Epub 2017 Apr 24. No abstract available.

PubMed [citation]
PMID:
28321935

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
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004570915.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys2672 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 28321935), which suggests that this may be a clinically significant amino acid residue. 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 549449). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 26787436). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2672 of the FBN1 protein (p.Cys2672Tyr).

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

Last Updated: Sep 29, 2024