NM_000138.5(FBN1):c.8522A>T (p.Glu2841Val) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 29, 2023
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:: RCV003789393.2

Allele description [Variation Report for NM_000138.5(FBN1):c.8522A>T (p.Glu2841Val)]

NM_000138.5(FBN1):c.8522A>T (p.Glu2841Val)

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.8522A>T (p.Glu2841Val)

HGVS:

NC_000015.10:g.48411084T>A
NG_008805.2:g.239705A>T
NM_000138.5:c.8522A>TMANE SELECT
NM_001406716.1:c.8522A>T
NP_000129.3:p.Glu2841Val
NP_000129.3:p.Glu2841Val
NP_001393645.1:p.Glu2841Val
LRG_778t1:c.8522A>T
LRG_778:g.239705A>T
LRG_778p1:p.Glu2841Val
NC_000015.9:g.48703281T>A
NM_000138.4:c.8522A>T

Protein change:

E2841V

Molecular consequence:

NM_000138.5:c.8522A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406716.1:c.8522A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Marfan syndrome (MFS)
Synonyms:: MARFAN SYNDROME, TYPE I; Marfan syndrome type 1; Marfan's syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007947; MedGen: C0024796; Orphanet: 284963; Orphanet: 558; OMIM: 154700

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
SCV004575081	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 29, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31536524, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004575081

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 29, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

NGS analysis in Marfan syndrome spectrum: Combination of rare and common genetic variants to improve genotype-phenotype correlation analysis.

Gentilini D, Oliveri A, Fazia T, Pini A, Marelli S, Bernardinelli L, Di Blasio AM.

PLoS One. 2019;14(9):e0222506. doi: 10.1371/journal.pone.0222506.

PubMed [citation]

PMID:: 31536524
PMCID:: PMC6752800

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004575081.1

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

Description

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (PMID: 31536524). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 2841 of the FBN1 protein (p.Glu2841Val).

#	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: Sep 29, 2024

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