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NM_000138.5(FBN1):c.3463G>A (p.Asp1155Asn) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Aug 5, 2021
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV002460054.5

Allele description [Variation Report for NM_000138.5(FBN1):c.3463G>A (p.Asp1155Asn)]

NM_000138.5(FBN1):c.3463G>A (p.Asp1155Asn)

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.3463G>A (p.Asp1155Asn)
Other names:
p.D1155N:GAC>AAC
HGVS:
  • NC_000015.10:g.48487312C>T
  • NG_008805.2:g.163477G>A
  • NM_000138.5:c.3463G>AMANE SELECT
  • NP_000129.3:p.Asp1155Asn
  • NP_000129.3:p.Asp1155Asn
  • LRG_778t1:c.3463G>A
  • LRG_778:g.163477G>A
  • LRG_778p1:p.Asp1155Asn
  • NC_000015.9:g.48779509C>T
  • NM_000138.4:c.3463G>A
Protein change:
D1155N
Links:
dbSNP: rs794728204
NCBI 1000 Genomes Browser:
rs794728204
Molecular consequence:
  • NM_000138.5:c.3463G>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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002618034Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Apr 3, 2020) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV003837673CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Aug 5, 2021) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms.

Milewicz DM, Michael K, Fisher N, Coselli JS, Markello T, Biddinger A.

Circulation. 1996 Dec 1;94(11):2708-11.

PubMed [citation]
PMID:
8941093

Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy.

Biggin A, Holman K, Brett M, Bennetts B, Adès L.

Hum Mutat. 2004 Jan;23(1):99.

PubMed [citation]
PMID:
14695540
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002618034.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The alteration results in an amino acid change:_x000D_ _x000D_ The c.3463G>A (p.D1155N) alteration is located in exon 28 (coding exon 27) of the FBN1 gene. This change occurs in the last base pair of coding exon 27, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration causes the aspartic acid (D) at amino acid position 1155 to be replaced by an asparagine (N). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.3463G>A alteration was observed in 0.0032% (1/31,402) of total alleles studied. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been reported in multiple individuals in association with Marfan syndrome and related features including ectopia lentis and aortic disease (Milewicz, 1996; Biggin, 2004; Comeglio, 2007; Stheneur, 2009; Aragon-Martin, 2010). Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ In one study utilizing in vitro analyses, this alteration did not significantly impact RNA splicing but demonstrated less fibrillin-1 deposition in the extracellular matrix compared with control cells (Milewicz, 1996). The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ BayesDel in silico prediction for the p.D1155N alteration is inconclusive. Based on the BDGP and ESEfinder splice site in silico tools, this alteration is predicted to weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.

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

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV003837673.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 22, 2024