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

gnomAD frequency: 0.00030  dbSNP: rs183306990

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000268396	SCV003933669	benign	Marfan syndrome	2023-06-15	reviewed by expert panel	curation	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035207	SCV000058851	benign	not specified	2024-01-16	criteria provided, single submitter	clinical testing	The p.Thr1547Ile variant in FBN1 is classified as benign because it has been identified in 0.2% (37/15268) of Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant was classified as Benign on Jun 15, 2023 by the ClinGen-approved FBN1 Variant Curation expert panel (Variation ID 42367). ACMG/AMP Criteria applied: BA1.
Illumina Laboratory Services, Illumina	RCV000307321	SCV000392337	likely benign	MASS syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000366645	SCV000392338	likely benign	Acromicric dysplasia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000396472	SCV000392339	likely benign	Ectopia lentis	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000303714	SCV000392340	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000358405	SCV000392341	likely benign	Stiff skin syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000268396	SCV000392342	likely benign	Marfan syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000323350	SCV000392343	likely benign	Geleophysic dysplasia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000354806	SCV000392344	likely benign	Weill-Marchesani syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000559382	SCV000627926	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-27	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000268396	SCV000781376	uncertain significance	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000303714	SCV001355732	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-23	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035207	SCV001362385	likely benign	not specified	2021-05-10	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4640C>T (p.Thr1547Ile) results in a non-conservative amino acid change located in the a TGF-beta binding (TB) domain (IPR017878) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 152182 control chromosomes, predominantly at a frequency of 0.0024 within the Latino subpopulation in the gnomAD v3 (whole genomes) database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.4640C>T has been reported in the literature in a Latino individual with suspected Marfan Syndrome who was diagnosed based on the old Ghent criteria, however no phenotype details (or co-segregation data) were provided (Lerner-Ellis_ 2014). The variant was also reported in a patient with aortic aneurysm, however this patient also carried a truncating FBN1 variant (FBN1 c.3193delG ,p.Glu1065fsX23) that could explain the phenotype (Weerakkody_2018), thus providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A recent study combining ACMG criteria with FBN1 gene-specific knowledge (i.e. considering critical FBN1 regions and appropriate minor allele frequency (MAF) cutoffs), classified the variant as likely benign (Baudhuin_2019). Four other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509492	SCV001716231	uncertain significance	not provided	2019-04-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001509492	SCV001747119	uncertain significance	not provided	2021-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001509492	SCV001787637	likely benign	not provided	2021-03-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31227806, 29543232, 24793577)
Ambry Genetics	RCV000303714	SCV002640266	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-06-02	criteria provided, single submitter	clinical testing	The p.T1547I variant (also known as c.4640C>T), located in coding exon 37 of the FBN1 gene, results from a C to T substitution at nucleotide position 4640. The threonine at codon 1547 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in a subject with features of Marfan syndrome (Lerner-Ellis JP et al. Mol Genet Metab, 2014 Jun;112:171-6). This amino acid position is not well 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 alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004534731	SCV004121134	uncertain significance	FBN1-related disorder	2023-02-21	criteria provided, single submitter	clinical testing	The FBN1 c.4640C>T variant is predicted to result in the amino acid substitution p.Thr1547Ile. This variant has been reported in individuals with Marfan syndrome or features of Marfan syndrome (Tables S1 and S6, Lerner-Ellis et al. 2014. PubMed ID: 24793577; Supplementary Tables, Weerakkody et al. 2018. PubMed ID: 29543232; Table S1, Baudhuin et al. 2019. PubMed ID: 31227806). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-48760242-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, raning from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/42367/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000268396	SCV004814706	uncertain significance	Marfan syndrome	2024-02-05	criteria provided, single submitter	clinical testing	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.