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NM_000138.5(FBN1):c.4096G>A (p.Glu1366Lys) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Mar 22, 2022
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:
RCV000770671.7

Allele description [Variation Report for NM_000138.5(FBN1):c.4096G>A (p.Glu1366Lys)]

NM_000138.5(FBN1):c.4096G>A (p.Glu1366Lys)

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.4096G>A (p.Glu1366Lys)
Other names:
p.E1366K:GAA>AAA; p.Glu1366Lys
HGVS:
  • NC_000015.10:g.48474369C>T
  • NG_008805.2:g.176420G>A
  • NM_000138.5:c.4096G>AMANE SELECT
  • NP_000129.3:p.Glu1366Lys
  • NP_000129.3:p.Glu1366Lys
  • LRG_778t1:c.4096G>A
  • LRG_778:g.176420G>A
  • LRG_778p1:p.Glu1366Lys
  • NC_000015.9:g.48766566C>T
  • NM_000138.4:c.4096G>A
Protein change:
E1366K
Links:
dbSNP: rs763449629
NCBI 1000 Genomes Browser:
rs763449629
Molecular consequence:
  • NM_000138.5:c.4096G>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
SCV000902130CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Mar 22, 2022) 		germlineclinical testing

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

SCV002632067Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Nov 6, 2020) 		germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

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 (12)

Details of each submission

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV000902130.4

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

From Ambry Genetics, SCV002632067.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

The p.E1366K pathogenic mutation (also known as c.4096G>A), located in coding exon 33 of the FBN1 gene, results from a G to A substitution at nucleotide position 4096. The glutamic acid at codon 1366 is replaced by lysine, an amino acid with similar properties, and is located in the cbEGF-like domain #19. This variant has been reported in classical Marfan syndrome cases and in individuals with ectopia lentis and skeletal findings but who lacked typical cardiac findings (Biggin A et al. Hum Mutat, 2004 Jan;23:99; Comeglio P et al. Hum Mutat, 2007 Sep;28:928; Baumgartner C et al. Methods Inf Med, 2005;44:487-97; Pees C et al. Clin Genet, 2014 Dec;86:552-7; Proost D et al. Hum Mutat, 2015 Aug;36:808-14). This variant was more recently reported as de novo in a child with ectopia lentis and mild aortic dilation (Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637). 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 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: Sep 29, 2024