NM_000138.5(FBN1):c.4057G>A (p.Gly1353Arg) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 22, 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:: RCV002532845.3

Allele description [Variation Report for NM_000138.5(FBN1):c.4057G>A (p.Gly1353Arg)]

NM_000138.5(FBN1):c.4057G>A (p.Gly1353Arg)

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.4057G>A (p.Gly1353Arg)

HGVS:

NC_000015.10:g.48474558C>T
NG_008805.2:g.176231G>A
NM_000138.5:c.4057G>AMANE SELECT
NP_000129.3:p.Gly1353Arg
NP_000129.3:p.Gly1353Arg
LRG_778t1:c.4057G>A
LRG_778:g.176231G>A
LRG_778p1:p.Gly1353Arg
NC_000015.9:g.48766755C>T
NM_000138.4:c.4057G>A

Protein change:

G1353R

Links:

dbSNP: rs187177496

NCBI 1000 Genomes Browser:

rs187177496

Molecular consequence:

NM_000138.5:c.4057G>A - 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
SCV003517572	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19293843, 31211624, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003517572

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 22, 2023)

germline

clinical testing

PubMed (3)
[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

Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene.

Stheneur C, Collod-Béroud G, Faivre L, Buyck JF, Gouya L, Le Parc JM, Moura B, Muti C, Grandchamp B, Sultan G, Claustres M, Aegerter P, Chevallier B, Jondeau G, Boileau C.

Eur J Hum Genet. 2009 Sep;17(9):1121-8. doi: 10.1038/ejhg.2009.36. Epub 2009 Mar 18.

PubMed [citation]

PMID:: 19293843
PMCID:: PMC2986588

Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection.

Wolford BN, Hornsby WE, Guo D, Zhou W, Lin M, Farhat L, McNamara J, Driscoll A, Wu X, Schmidt EM, Norton EL, Mathis MR, Ganesh SK, Douville NJ, Brummett CM, Kitzman J, Chen YE, Kim K, Deeb GM, Patel H, Eagle KA, Milewicz DM, et al.

Circ Genom Precis Med. 2019 Jun;12(6):e002476. doi: 10.1161/CIRCGEN.118.002476. Epub 2019 Jun 18.

PubMed [citation]

PMID:: 31211624
PMCID:: PMC6582991

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003517572.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly1353 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 521833). This missense change has been observed in individuals with clinical features of FBN1-related conditions (PMID: 19293843, 31211624; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1353 of the FBN1 protein (p.Gly1353Arg).

#	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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