NM_000138.5(FBN1):c.4640C>T (p.Thr1547Ile) AND Marfan syndrome

Germline classification:: Benign (4 submissions)
Last evaluated:: Jun 15, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000268396.11

Allele description [Variation Report for NM_000138.5(FBN1):c.4640C>T (p.Thr1547Ile)]

NM_000138.5(FBN1):c.4640C>T (p.Thr1547Ile)

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.4640C>T (p.Thr1547Ile)

Other names:

NM_000138.5(FBN1):c.4640C>T

HGVS:

NC_000015.10:g.48468045G>A
NG_008805.2:g.182744C>T
NM_000138.5:c.4640C>TMANE SELECT
NP_000129.3:p.Thr1547Ile
NP_000129.3:p.Thr1547Ile
LRG_778t1:c.4640C>T
LRG_778:g.182744C>T
LRG_778p1:p.Thr1547Ile
NC_000015.9:g.48760242G>A
NM_000138.4:c.4640C>T
c.4640C>T

Protein change:

T1547I

Links:

dbSNP: rs183306990

NCBI 1000 Genomes Browser:

rs183306990

Molecular consequence:

NM_000138.5:c.4640C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Recent activity

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BioAssay by Target (List) for Gene (Select 2903) (14)
PubChem BioAssay
PopSet for PopSet (Select 297528206) (0)
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OMIM Links for Gene (Select 2903) (2)
OMIM
glutamate receptor ionotropic, NMDA 2A isoform X4 [Homo sapiens]
glutamate receptor ionotropic, NMDA 2A isoform X4 [Homo sapiens]
gi|2462548652|ref|XP_054236126.1|

Protein
PREDICTED: Homo sapiens glutamate ionotropic receptor NMDA type subunit 2A (GRIN...
PREDICTED: Homo sapiens glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A), transcript variant X3, mRNA
gi|2462548649|ref|XM_054380150.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000392342	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Likely benign (Jun 14, 2016)	germline	clinical testing	ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000781376	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003933669	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (Assertion Criteria VCEP FBN1 Version 1)	Benign (Jun 15, 2023)	germline	curation	Citation Link,
SCV004814706	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 5, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24793577, 29543232, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	42	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

The spectrum of FBN1, TGFβR1, TGFβR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD).

Lerner-Ellis JP, Aldubayan SH, Hernandez AL, Kelly MA, Stuenkel AJ, Walsh J, Joshi VA.

Mol Genet Metab. 2014 Jun;112(2):171-6. doi: 10.1016/j.ymgme.2014.03.011. Epub 2014 Apr 2.

PubMed [citation]

PMID:: 24793577

Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta.

Weerakkody R, Ross D, Parry DA, Ziganshin B, Vandrovcova J, Gampawar P, Abdullah A, Biggs J, Dumfarth J, Ibrahim Y; Yale Aortic Institute Data and Repository Team., Bicknell C, Field M, Elefteriades J, Cheshire N, Aitman TJ.

Genet Med. 2018 Nov;20(11):1414-1422. doi: 10.1038/gim.2018.27. Epub 2018 Mar 15.

PubMed [citation]

PMID:: 29543232
PMCID:: PMC6004315

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000392342.2

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

#	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

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781376.1

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

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

From ClinGen FBN1 Variant Curation Expert Panel, ClinGen, SCV003933669.1

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

Description

The NM_00138 c.4640C>T, is a missense variant in FBN1 predicted to cause a substitution of a threonine by isoleucine at amino acid 1547 (p.Thr1547Ile). This variant was found one proband with Marfan syndrome (PMID 24793577) and in three apparently unrelated probands with features of Marfan syndrome (PMID 24793577, internal data). In one of these individuals with features of Marfan syndrome, this variant was also detected in the proband’s mother and sister, both of whom had a systemic score of 9, however relatedness of these individuals was not confirmed (internal data). This variant was also identified in an individual with features of Marfan syndrome but no diagnosis who also carried a pathogenic variant in FBN1, c.3193delG p.Glu1065Lysfs*23 (PMID 29543232). The variant in FBN1 has been reported 17 times in ClinVar: 6 times as uncertain significance and 11 times as likely benign (Variation ID: 42367). This variant has been identified in 37 individuals of Latino/Admixed American origin in gnomAD v3.1.2 (MAF: 0.24%) (BA1; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.375). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1.

#	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

From All of Us Research Program, National Institutes of Health, SCV004814706.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	42	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces threonine with isoleucine at codon 1547 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual with suspected Marfan syndrome (PMID: 24793577) and in an individual with aneurysm of the thoracic aorta (PMID: 29543232). This variant has been identified in 9/282682 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	108544	not provided	not provided		42	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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