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NM_000138.5(FBN1):c.4243T>C (p.Cys1415Arg) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 3, 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:
RCV002314309.9

Allele description [Variation Report for NM_000138.5(FBN1):c.4243T>C (p.Cys1415Arg)]

NM_000138.5(FBN1):c.4243T>C (p.Cys1415Arg)

Genes:
LOC126862124:CDK7 strongly-dependent group 2 enhancer GRCh37_chr15:48764566-48765765 [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.4243T>C (p.Cys1415Arg)
HGVS:
  • NC_000015.10:g.48472644A>G
  • NG_008805.2:g.178145T>C
  • NM_000138.5:c.4243T>CMANE SELECT
  • NP_000129.3:p.Cys1415Arg
  • NP_000129.3:p.Cys1415Arg
  • LRG_778t1:c.4243T>C
  • LRG_778:g.178145T>C
  • LRG_778p1:p.Cys1415Arg
  • NC_000015.9:g.48764841A>G
  • NM_000138.4:c.4243T>C
Protein change:
C1415R
Links:
dbSNP: rs1555397557
NCBI 1000 Genomes Browser:
rs1555397557
Molecular consequence:
  • NM_000138.5:c.4243T>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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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000738779Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(May 3, 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, SCV000738779.5

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

Description

The p.C1415R variant (also known as c.4243T>C), located in coding exon 34 of the FBN1 gene, results from a T to C substitution at nucleotide position 4243. The cysteine at codon 1415 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is located in the cb EGF-like #20 domain, and 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). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive EGF/cbEGF domain #20.This variant was not reported in population-based 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 majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Nov 10, 2024