NM_000138.5(FBN1):c.2093C>T (p.Pro698Leu) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 12, 2023
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:: RCV001184007.12

Allele description [Variation Report for NM_000138.5(FBN1):c.2093C>T (p.Pro698Leu)]

NM_000138.5(FBN1):c.2093C>T (p.Pro698Leu)

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.2093C>T (p.Pro698Leu)

HGVS:

NC_000015.10:g.48503807G>A
NG_008805.2:g.146982C>T
NM_000138.5:c.2093C>TMANE SELECT
NP_000129.3:p.Pro698Leu
NP_000129.3:p.Pro698Leu
LRG_778t1:c.2093C>T
LRG_778:g.146982C>T
LRG_778p1:p.Pro698Leu
NC_000015.9:g.48796004G>A
NM_000138.4:c.2093C>T

Protein change:

P698L

Links:

dbSNP: rs764827921

NCBI 1000 Genomes Browser:

rs764827921

Molecular consequence:

NM_000138.5:c.2093C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000319951	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Aug 14, 2015)	germline	clinical testing	Citation Link,
SCV001349875	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 12, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26621581, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000319951

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Uncertain significance
(Aug 14, 2015)

germline

clinical testing

Citation Link,

SCV001349875

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 12, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections.

Regalado ES, Guo DC, Santos-Cortez RL, Hostetler E, Bensend TA, Pannu H, Estrera A, Safi H, Mitchell AL, Evans JP, Leal SM, Bamshad M, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics., Milewicz DM.

Clin Genet. 2016 Jun;89(6):719-23. doi: 10.1111/cge.12702. Epub 2016 Jan 20.

PubMed [citation]

PMID:: 26621581
PMCID:: PMC4873375

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

Details of each submission

From Ambry Genetics, SCV000319951.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

The p.P698L variant (also known as c.2093C>T), located in coding exon 16 of the FBN1 gene, results from a C to T substitution at nucleotide position 2093. The proline at codon 698 is replaced by leucine, an amino acid with a few similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6493 samples (12986 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001349875.3

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

Description

This missense variant replaces proline with leucine at codon 698 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with thoracic aortic aneurysm and dissection, who showed no features of Marfan syndrome and lacked family history of Marfan syndrome (PMID: 26621581). This variant has been identified in 4/282774 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: Apr 20, 2024

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