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NM_000138.5(FBN1):c.4471T>A (p.Cys1491Ser) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 6, 2021
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:
RCV002328489.2

Allele description [Variation Report for NM_000138.5(FBN1):c.4471T>A (p.Cys1491Ser)]

NM_000138.5(FBN1):c.4471T>A (p.Cys1491Ser)

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.4471T>A (p.Cys1491Ser)
HGVS:
  • NC_000015.10:g.48468523A>T
  • NG_008805.2:g.182266T>A
  • NM_000138.5:c.4471T>AMANE SELECT
  • NM_001406716.1:c.4471T>A
  • NP_000129.3:p.Cys1491Ser
  • NP_000129.3:p.Cys1491Ser
  • NP_001393645.1:p.Cys1491Ser
  • LRG_778t1:c.4471T>A
  • LRG_778:g.182266T>A
  • LRG_778p1:p.Cys1491Ser
  • NC_000015.9:g.48760720A>T
  • NM_000138.4:c.4471T>A
Protein change:
C1491S
Molecular consequence:
  • NM_000138.5:c.4471T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406716.1:c.4471T>A - 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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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002636684Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Dec 6, 2021) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Ambry Genetics, SCV002636684.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.C1491S variant (also known as c.4471T>A), located in coding exon 36 of the FBN1 gene, results from a T to A substitution at nucleotide position 4471. The cysteine at codon 1491 is replaced by serine, an amino acid with dissimilar properties. This variant has been detected in an individual with features consistent with Marfan syndrome (MFS) or fibrillinopathy and has been determined to be the result of a de novo mutation or germline mosaicism in one individual (Ambry internal data). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive cbEGF domain #22. 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: May 1, 2024