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NM_000138.5(FBN1):c.6505G>A (p.Glu2169Lys) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 24, 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:
RCV003809216.2

Allele description [Variation Report for NM_000138.5(FBN1):c.6505G>A (p.Glu2169Lys)]

NM_000138.5(FBN1):c.6505G>A (p.Glu2169Lys)

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.6505G>A (p.Glu2169Lys)
HGVS:
  • NC_000015.10:g.48434705C>T
  • NG_008805.2:g.216084G>A
  • NM_000138.5:c.6505G>AMANE SELECT
  • NM_001406716.1:c.6505G>A
  • NP_000129.3:p.Glu2169Lys
  • NP_000129.3:p.Glu2169Lys
  • NP_001393645.1:p.Glu2169Lys
  • LRG_778t1:c.6505G>A
  • LRG_778:g.216084G>A
  • LRG_778p1:p.Glu2169Lys
  • NC_000015.9:g.48726902C>T
  • NM_000138.4:c.6505G>A
Protein change:
E2169K
Molecular consequence:
  • NM_000138.5:c.6505G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406716.1:c.6505G>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
SCV004595387Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Oct 24, 2023)
germlineclinical testing

PubMed (3)
[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

Fibrillin degradation by matrix metalloproteinases: implications for connective tissue remodelling.

Ashworth JL, Murphy G, Rock MJ, Sherratt MJ, Shapiro SD, Shuttleworth CA, Kielty CM.

Biochem J. 1999 May 15;340 ( Pt 1)(Pt 1):171-81.

PubMed [citation]
PMID:
10229672
PMCID:
PMC1220235

Genetic testing in patients with aortic aneurysms/dissections: a novel genotype/phenotype correlation?

Waldmüller S, Müller M, Warnecke H, Rees W, Schöls W, Walterbusch G, Ennker J, Scheffold T.

Eur J Cardiothorac Surg. 2007 Jun;31(6):970-5. Epub 2007 Apr 5.

PubMed [citation]
PMID:
17418587
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004595387.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2169 of the FBN1 protein (p.Glu2169Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Marfan syndrome and/or thoracic aortic aneurysm and dissection (Invitae). It has also been observed to segregate with disease in related individuals. 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect FBN1 function (PMID: 10229672). This variant disrupts the p.Glu2169 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 17418587), which suggests that this may be a clinically significant amino acid residue. 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.

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

Last Updated: Sep 29, 2024