NM_000138.5(FBN1):c.6806T>C (p.Ile2269Thr) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 2, 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:: RCV000534047.17

Allele description [Variation Report for NM_000138.5(FBN1):c.6806T>C (p.Ile2269Thr)]

NM_000138.5(FBN1):c.6806T>C (p.Ile2269Thr)

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.6806T>C (p.Ile2269Thr)

HGVS:

NC_000015.10:g.48430736A>G
NG_008805.2:g.220053T>C
NM_000138.5:c.6806T>CMANE SELECT
NP_000129.3:p.Ile2269Thr
NP_000129.3:p.Ile2269Thr
LRG_778t1:c.6806T>C
LRG_778:g.220053T>C
LRG_778p1:p.Ile2269Thr
NC_000015.9:g.48722933A>G
NM_000138.4:c.6806T>C
c.6806T>C

Protein change:

I2269T

Links:

dbSNP: rs193922228

NCBI 1000 Genomes Browser:

rs193922228

Molecular consequence:

NM_000138.5:c.6806T>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
SCV000627974	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 2, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10464652, 12203992, 16342915, 18435798, 19159394, 19293843, 25907466, 27611364, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000627974

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 2, 2023)

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

Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders.

Liu WO, Oefner PJ, Qian C, Odom RS, Francke U.

Genet Test. 1997-1998;1(4):237-42.

PubMed [citation]

PMID:: 10464652

TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies.

Katzke S, Booms P, Tiecke F, Palz M, Pletschacher A, Türkmen S, Neumann LM, Pregla R, Leitner C, Schramm C, Lorenz P, Hagemeier C, Fuchs J, Skovby F, Rosenberg T, Robinson PN.

Hum Mutat. 2002 Sep;20(3):197-208.

PubMed [citation]

PMID:: 12203992

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000627974.9

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2269 of the FBN1 protein (p.Ile2269Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 10464652, 12203992, 16342915, 18435798, 19159394, 19293843, 25907466, 27611364). ClinVar contains an entry for this variant (Variation ID: 36107). 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%. 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: Jun 9, 2024

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