NM_000138.5(FBN1):c.2722T>C (p.Cys908Arg) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 20, 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:: RCV002429487.2

Allele description [Variation Report for NM_000138.5(FBN1):c.2722T>C (p.Cys908Arg)]

NM_000138.5(FBN1):c.2722T>C (p.Cys908Arg)

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.2722T>C (p.Cys908Arg)

HGVS:

NC_000015.10:g.48494210A>G
NG_008805.2:g.156579T>C
NM_000138.5:c.2722T>CMANE SELECT
NP_000129.3:p.Cys908Arg
NP_000129.3:p.Cys908Arg
LRG_778t1:c.2722T>C
LRG_778:g.156579T>C
LRG_778p1:p.Cys908Arg
NC_000015.9:g.48786407A>G
NM_000138.4:c.2722T>C

Protein change:

C908R

Links:

dbSNP: rs1060501021

NCBI 1000 Genomes Browser:

rs1060501021

Molecular consequence:

NM_000138.5:c.2722T>C - missense variant - [Sequence Ontology: SO:0001583]

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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Homo sapiens tight junction protein 1 (TJP1), transcript variant 7, mRNA
Homo sapiens tight junction protein 1 (TJP1), transcript variant 7, mRNA
gi|1239290994|ref|NM_001355013.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002741464	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 20, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12203987, 12203992, 17701892, 19293843, 19353630, 24698609, 26281765 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002741464

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 20, 2020)

germline

clinical testing

PubMed (7)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies.

Robinson PN, Booms P, Katzke S, Ladewig M, Neumann L, Palz M, Pregla R, Tiecke F, Rosenberg T.

Hum Mutat. 2002 Sep;20(3):153-61. Review.

PubMed [citation]

PMID:: 12203987

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 (7)

Details of each submission

From Ambry Genetics, SCV002741464.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.C908R pathogenic mutation (also known as c.2722T>C), located in coding exon 22 of the FBN1 gene, results from a T to C substitution at nucleotide position 2722. The cysteine at codon 908 is replaced by arginine, an amino acid with highly dissimilar properties. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This variant has been detected in individuals with classic Marfan syndrome and with Marfan-like findings (Katzke S et al. Hum. Mutat., 2002 Sep;20:197-208; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8; Khan AO et al. J AAPOS, 2014 Apr;18:134-9). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide in the structurally sensitive hybrid motif #02 domain. Furthermore, alternate amino acid substitutions at this codon, p.C908Y and p.C908G, have also been reported in Marfan syndrome cohorts, suggesting this as a hotspot position (Judge DP et al. Am J Med Genet. 2001;99:39-47; Wang WJ et al. J Mol Med. 2013;91:37-47; Haine E et al. J Bone Miner Res. 2015;30:1369-76). 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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