rs727503054

Positions:

• chr15-48420752-A-G
• chr15-48420752-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PP2 PP3_Moderate PP5_Very_Strong

The NM_000138.5(FBN1):​c.7754T>C​(p.Ile2585Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 9.32

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a domain EGF-like 45; calcium-binding (size 39) in uniprot entity FBN1_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_000138.5
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ 5.0644 (greater than the threshold 3.09). Trascript score misZ 8.1787 (greater than threshold 3.09). GenCC has associacion of gene with MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• PP5: Variant 15-48420752-A-G is Pathogenic according to our data. Variant chr15-48420752-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 163462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48420752-A-G is described in Lovd as [Likely_pathogenic]. Variant chr15-48420752-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.7754T>C	p.Ile2585Thr	missense_variant	63/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.7754T>C	p.Ile2585Thr	missense_variant	62/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.7754T>C	p.Ile2585Thr	missense_variant	63/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250918 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461798 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:27

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Feb 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 16, 2023	This missense variant replaces isoleucine with threonine at codon 2585 in the EGF-like calcium-binding domain of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in many individuals affected with Marfan syndrome (PMID: 19293843, 24161884, 24833718, 25907466, 26333736, 27146836, 31751304, 32679894) and in individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 28855619, 30675029, 30739908, 34498425), including two individuals where the variant was observed to be de novo (PMID: 29357934, 34498425). This variant has been shown to segregate with disease in three families (PMID: 27146836, 27724990, 31751304). In one family, six carriers across three generations showed remarkable variability in clinical features, ranging from isolated scoliosis, aneurysm of the abdominal aorta, thoracic aortic aneurysm and aortic dissection through Marfan syndrome (PMID: 27146836). This variant has been identified in 4/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated EGF-like domain (Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Marfan syndrome or other Marfan syndrome related phenotypes (ClinVar, VCGS, PMID: 11700157). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PS4, PS1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 14, 2018	The p.Ile2585Thr variant in FBN1 has been reported in >15 individuals with clini cal features of Marfan syndrome (Liu 1997, Loeys 2001, Biggin 2004, Comeglio 200 7, Howarth 2007, Stheneur 2009, Soylen 2009, Ogawa 2011, Aalberts 2014, Buchan 2 014, Haller 2015, Proost 2015, Yang 2016, Poninska 2016, LMM unpublished data) a nd segregated with disease in 5 affected relatives from two families (Howarth 20 07, Poninska 2016). This variant has also been reported by other clinical labora tories in ClinVar (Variation ID 163462), including a de novo occurrence in one i ndividual referred for Marfan/TAAD testing in one laboratory (SCV000233916.8). I t has been identified in 1/30782 South Asian and 1/33572 Latino chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727503054). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, this v ariant meets criteria to be classified as pathogenic for Marfan syndrome in an a utosomal dominant manner based upon presence in multiple affected individuals, s egregation studies, and de novo occurrence. ACMG/AMP Criteria applied: PS4, PM2, PP1_Moderate, PM6 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Apr 02, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 10, 2015	- -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2021	The FBN1 c.7754T>C; p.Ile2585Thr variant (rs727503054) is reported in the literature in multiple individuals affected with Marfan syndrome (MFS) or MFS-related phenotypes (Becerra-Munoz 2018, Biggin 2004, Collod-Beroud 2003, Comeglio 2007, Fang 2017, Haller 2015, Liu 1997-1998, Loeys 2001, Poninska 2016, Yang 2016). This variant is reported in ClinVar (Variation ID: 163462), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 2585 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious REVEL: 0.642). Based on available information, the p.Ile2585Thr variant is considered to be pathogenic. References: Becerra-Munoz VM et al. The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. Orphanet J Rare Dis. 2018 Jan 22;13(1):16. PubMed: 29357934. Biggin A et al. Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat. 2004 Jan;23(1):99. PMID: 14695540. Collod-Beroud G et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 2003 Sep;22(3):199-208. PMID: 12938084. Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. PMID: 17657824. Fang M et al. Identification of Novel Clinically Relevant Variants in 70 Southern Chinese patients with Thoracic Aortic Aneurysm and Dissection by Next-generation Sequencing. Sci Rep. 2017 Aug 30;7(1):10035. PMID: 28855619. Haller G et al. Genetic Risk for Aortic Aneurysm in Adolescent Idiopathic Scoliosis. J Bone Joint Surg Am. 2015 Sep 2;97(17):1411-7. PMID: 26333736. Liu WO et al. Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders. Genet Test. 1997-1998;1(4):237-42. PMID: 10464652. Loeys B et al. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001 Nov 12;161(20):2447-54. PMID: 11700157 Poninska JK et al. Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations. J Transl Med. 2016 May 4;14(1):115. PMID: 27146836. Yang H et al. Genetic testing of 248 Chinese aortopathy patients using a panel assay. Sci Rep. 2016 Sep 9;6:33002. PMID: 27611364. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 23, 2021	PP1_moderate, PP2, PP5, PM2_supporting, PM6, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2021	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 14695540, 17627385, 17657824, 27611364, 31098894, 31211626, 31751304, 32123317, 30739908, 32866347, 10464652, 21907952, 11933199, 24833718, 19293843, 24161884, 26333736, 27146836, 28855619, 27724990, 19159394, 29357934, 30675029, 25907466, 12938084, 12203992, 12203987, 31447099, 33483584, 32679894, 11700157) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	Nov 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 04, 2022	The p.I2585T pathogenic mutation (also known as c.7754T>C), located in coding exon 62 of the FBN1 gene, results from a T to C substitution at nucleotide position 7754. The isoleucine at codon 2585 is replaced by threonine, an amino acid with some similar properties, and is located in the cb EGF-like #41 domain. This alteration has been reported in numerous individuals with Marfan syndrome (MFS) and MFS-related phenotypes from a variety of ethnic backgrounds (Loeys B et al. Arch Intern Med. 2001;161(20):2447-2454; Biggin A et al. Hum Mutat. 2004;23(1):99; Soylen B et al. Clin Genet. 2009;75(3):265-270; Yang H et al. Sci Rep, 2016 Sep;6:33002). In one family, six relatives across three generations were reported to have this alteration with clinical features ranging from isolated scoliosis through complete MFS (Poninska JK et al. J Transl Med, 2016 May;14:115). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jan 18, 2022	This variant has been reported in the literature in numerous individuals with a clinical diagnosis or features of Marfan syndrome, segregating with disease in at least 2 affected family members, and has also been identified in the de novo state (Selected publications: Loeys 2001 PMID:11700157, Stheneur 2009 PMID:19293843, Haller 2015 PMID:26333736, Fang 2016 PMID:28855619, Poninska 2016 PMID:27146836, Yang 2016 PMID:27611364, Becerra Munoz 2018 PMID:29357934, Damrauer 2019 PMID:31211626, Renner 2019 PMID:30675029, Ferreira de Assis Funari 2020 PMID:31751304, Stark 2020 PMID:32679894). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic or Likely Pathogenic (Variation ID:163462). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, this variant is classified as Pathogenic. -

Connective tissue dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Jan 17, 2023

Heterozygous variant NM_000138:c.7754T>C (p.Ile2585Thr) in FBN1 gene was found on the WES data in female proband (65 y.o., Caucasian) with Connective tissue dysplasia and aortic dissection. This variant has been reported in over 30 articles with variable phenotypes. Clinvar contains entry on this variant (Variation ID: 163462). This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.00001594 (Date of access 17-01-2023). This variant has been reported in over several dozens of studies. In silico predictors are inconsistent in the results (varsome.com). In accordance with ACMG(2015) criteria and Proposal for a Disease- and Gene-Specific Guideline for the Interpretation of Sequenced Variants in the FBN1 Gene for Marfan Syndrome (PMID: 29875124), this variant is classified as Pathogenic with following criteria selected: PS4_Strong, PP5_Strong, PS5, PM2. -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 12, 2017

Variant summary: The FBN1 c.7754T>C (p.Ile2585Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution within a growth factor receptor cysteine-rich domain and a EGF-like calcium-binding domain (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent from the large control database ExAC (0/121220 control chromosomes). In the literature, numerous Marfan syndrome and Marfan syndrome-like patients have been identified as carriers of the variant, and segregation of the allele with disease in families has been observed (Stheneur_EJHG_2009; Howarth_GT_2007), though the allele may not be fully penetrant (Poninska_J Transl Med_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic or pathogenic. Taken together, this variant is classified as pathogenic. -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2585 of the FBN1 protein (p.Ile2585Thr). This variant is present in population databases (rs727503054, gnomAD 0.003%). This missense change has been observed in individual(s) with Marfan syndrome and a FBN1-related disease (PMID: 10464652, 11700157, 14695540, 17657824, 19293843, 24833718, 26333736; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 163462). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Aortic aneurysm;C0036439:Scoliosis;C0241240:Tall stature;C0271183:High myopia;C0856747:Ascending tubular aorta aneurysm;C1844820:Joint hypermobility Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 04, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.30	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.64
Sift	Benign	0.54	T
Sift4G	Benign	0.42	T
Vest4		0.65
MutPred		0.88		Loss of stability (P = 0.0076);
MVP		0.90
MPC		0.94
ClinPred		0.38	T
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727503054; hg19: chr15-48712949;