NM_000138.5(FBN1):c.4589G>C (p.Arg1530Pro) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 30, 2019
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:: RCV002314296.9

Allele description [Variation Report for NM_000138.5(FBN1):c.4589G>C (p.Arg1530Pro)]

NM_000138.5(FBN1):c.4589G>C (p.Arg1530Pro)

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.4589G>C (p.Arg1530Pro)

HGVS:

NC_000015.10:g.48468096C>G
NG_008805.2:g.182693G>C
NM_000138.5:c.4589G>CMANE SELECT
NP_000129.3:p.Arg1530Pro
NP_000129.3:p.Arg1530Pro
LRG_778t1:c.4589G>C
LRG_778:g.182693G>C
LRG_778p1:p.Arg1530Pro
NC_000015.9:g.48760293C>G
NM_000138.4:c.4589G>C

Protein change:

R1530P

Links:

dbSNP: rs778710767

NCBI 1000 Genomes Browser:

rs778710767

Molecular consequence:

NM_000138.5:c.4589G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000738758	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Dec 30, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11700157, 15062093 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000738758

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Dec 30, 2019)

germline

clinical testing

PubMed (2)
[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

Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome.

Loeys B, Nuytinck L, Delvaux I, De Bie S, De Paepe A.

Arch Intern Med. 2001 Nov 12;161(20):2447-54.

PubMed [citation]

PMID:: 11700157

Structure of the integrin binding fragment from fibrillin-1 gives new insights into microfibril organization.

Lee SS, Knott V, Jovanović J, Harlos K, Grimes JM, Choulier L, Mardon HJ, Stuart DI, Handford PA.

Structure. 2004 Apr;12(4):717-29.

PubMed [citation]

PMID:: 15062093
PMCID:: PMC5582136

Details of each submission

From Ambry Genetics, SCV000738758.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.R1530P variant (also known as c.4589G>C), located in coding exon 37 of the FBN1 gene, results from a G to C substitution at nucleotide position 4589. The arginine at codon 1530 is replaced by proline, an amino acid with dissimilar properties. This amino acid is involved in interfacial salt-bridge interactions (Lee SS et al. Structure, 2004 Apr;12:717-29), and internal structural analysis suggests that this variant will result in structural destabilization of the interface between domain cbEGF#22 and TB4. In addition, a mutation affecting the same amino acid (p.R1530C, c.4588C>T) has been reported in association with ectopia lentis and Marfan syndrome-related features (Loeys B et al. Arch Intern Med. 2001;161(20):2447-54). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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: Nov 3, 2024

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