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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:
42

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000392342Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification 20161018)
Likely benign
(Jun 14, 2016)
germlineclinical testing

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV000781376Center for Human Genetics, Inc, Center for Human Genetics, Inc
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Nov 1, 2016)
germlineclinical testing

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

SCV003933669ClinGen FBN1 Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(Assertion Criteria VCEP FBN1 Version 1)
Benign
(Jun 15, 2023)
germlinecuration

Citation Link,

SCV004814706All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain Significance
(Feb 5, 2024)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown42not providednot provided108544not providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

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

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided42not providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided42not providednot providednot provided

Last Updated: Sep 29, 2024