NM_000138.5(FBN1):c.8326C>T (p.Arg2776Ter) AND Familial thoracic aortic aneurysm and aortic dissection

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 3, 2022
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:: RCV002310993.8

Allele description

NM_000138.5(FBN1):c.8326C>T (p.Arg2776Ter)

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.8326C>T (p.Arg2776Ter)

Other names:

p.R2776X:CGA>TGA

HGVS:

NC_000015.10:g.48411280G>A
NG_008805.2:g.239509C>T
NM_000138.5:c.8326C>TMANE SELECT
NP_000129.3:p.Arg2776Ter
NP_000129.3:p.Arg2776Ter
LRG_778t1:c.8326C>T
LRG_778:g.239509C>T
LRG_778p1:p.Arg2776Ter
NC_000015.9:g.48703477G>A
NM_000138.4:c.8326C>T
NM_000138.5:c.8326C>T
p.Arg2776X
p.R2776*

Protein change:

R2776*; ARG2776TER

Links:

OMIM: 134797.0017; dbSNP: rs137854466

NCBI 1000 Genomes Browser:

rs137854466

Molecular consequence:

NM_000138.5:c.8326C>T - nonsense - [Sequence Ontology: SO:0001587]

Functional consequence:

variation affecting protein [Variation Ontology: 0002]

Observations:

Condition(s)

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
SCV000320556	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11826022, 19293843, 24982166, 25907466, 31098894, 31730815, 33059708, 7911051 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000320556

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Jan 3, 2022)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions.

Körkkö J, Kaitila I, Lönnqvist L, Peltonen L, Ala-Kokko L.

J Med Genet. 2002 Jan;39(1):34-41.

PubMed [citation]

PMID:: 11826022
PMCID:: PMC1734965

Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene.

Stheneur C, Collod-Béroud G, Faivre L, Buyck JF, Gouya L, Le Parc JM, Moura B, Muti C, Grandchamp B, Sultan G, Claustres M, Aegerter P, Chevallier B, Jondeau G, Boileau C.

Eur J Hum Genet. 2009 Sep;17(9):1121-8. doi: 10.1038/ejhg.2009.36. Epub 2009 Mar 18.

PubMed [citation]

PMID:: 19293843
PMCID:: PMC2986588

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000320556.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

The p.R2776* pathogenic mutation (also known as c.8326C>T), located in coding exon 65 of the FBN1 gene, results from a C to T substitution at nucleotide position 8326. This changes the amino acid from an arginine to a stop codon within coding exon 65. This alteration occurs at the 3' terminus of theFBN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 96 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration, which is also known as p.R1878*, c.5632C>T, has been reported in multiple individuals with Marfan syndrome (Hayward C et al. Hum. Mutat., 1994;3:159-62; Körkkö J et al. J. Med. Genet., 2002 Jan;39:34-41; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Jensen SA et al. Proc Natl Acad Sci U S A, 2014 Jul;111:10155-60; Proost D et al. Hum Mutat, 2015 Aug;36:808-14; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164; Stengl R et al. Orphanet J Rare Dis, 2020 10;15:290). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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