rs137854475

Positions:

chr15-48487155-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP2BA1BP5

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.3509G>A, is a missense variant in FBN1 predicted to cause a substitution of an arginine acid by histidine at amino acid 1170 (p.Arg1170His). This variant has been previously reported in several apparently unrelated individuals with Marfan syndrome (PMID 26787436, internal data), incomplete Marfan syndrome, including with skeletal features and/or mitral valve prolapse (PMID 7870075, 9837823, 17418587, 17627385, 17657824), in individuals with isolated thoracic aortic aneurysm and/or dissection (internal data) and in other phenotypes like arterial dissection and venous bleeding (internal data). This variant was found to segregate with disease in seven affected individuals with incomplete Marfan syndrome from three families (PMID 7870075, 9837823, internal data). This variant has been found to co-occur with different pathogenic variants in FBN1 (BP2), TGFBR1, and TGFRB2 (BP5) (internal data). This variant has been identified in 286 individuals of European non-Finnish origin (MAF: 0.2%) (BA1; https://gnomad.broadinstitute.org/, version 2.1.1). The variant in FBN1 has been reported 21 times in ClinVar: 16 times as likely benign and 5 times as uncertain significance (Variation ID: 16451). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.502). Functional studies, including in-vitro splicing analysis, found that this variant had no impact on splicing (PMID 21895641, 32123317). 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, BP2, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014215/MONDO:0007947/022

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 4 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:2U:7B:24O:1

Conservation

PhyloP100: 2.10

Variant links:

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]

FBN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.3509G>A	p.Arg1170His	missense_variant	29/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1 linkuse as main transcript	c.3509G>A	p.Arg1170His	missense_variant	28/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.3509G>A	p.Arg1170His	missense_variant	29/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

250

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00256

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00250

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00126

AC:

316

AN:

251438

Hom.:

AF XY:

0.00133

AC XY:

181

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00230

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00245

AC:

3584

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

1754

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00303

Gnomad4 OTH exome

AF:

0.00235

GnomAD4 genome

AF:

0.00164

AC:

250

AN:

152258

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00250

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00224

Hom.:

Bravo

AF:

0.00219

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00117

AC:

142

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00184

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2Uncertain:7Benign:24Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Marfan syndrome

Pathogenic:1Uncertain:3Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Feb 01, 2023	The NM_00138 c.3509G>A, is a missense variant in FBN1 predicted to cause a substitution of an arginine acid by histidine at amino acid 1170 (p.Arg1170His). This variant has been previously reported in several apparently unrelated individuals with Marfan syndrome (PMID 26787436, internal data), incomplete Marfan syndrome, including with skeletal features and/or mitral valve prolapse (PMID 7870075, 9837823, 17418587, 17627385, 17657824), in individuals with isolated thoracic aortic aneurysm and/or dissection (internal data) and in other phenotypes like arterial dissection and venous bleeding (internal data). This variant was found to segregate with disease in seven affected individuals with incomplete Marfan syndrome from three families (PMID 7870075, 9837823, internal data). This variant has been found to co-occur with different pathogenic variants in FBN1 (BP2), TGFBR1, and TGFRB2 (BP5) (internal data). This variant has been identified in 286 individuals of European non-Finnish origin (MAF: 0.2%) (BA1; https://gnomad.broadinstitute.org/, version 2.1.1). The variant in FBN1 has been reported 21 times in ClinVar: 16 times as likely benign and 5 times as uncertain significance (Variation ID: 16451). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.502). Functional studies, including in-vitro splicing analysis, found that this variant had no impact on splicing (PMID 21895641, 32123317). 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, BP2, BP5. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Likely pathogenic, flagged submission	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely benign, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FBN1: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 24, 2015	p.Arg1170His in exon 28 of FBN1: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (124/66684) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs137854475). Arginine (Arg) at position 1170 is not conserved in evolut ionarily distant species and at least 10 birds, reptiles, and fish carry a histi dine (His) at this position, supporting that this change may be tolerated. This variant has been identified by our laboratory in 6 individuals with features of Marfan syndrome; however, two of these individuals were compound heterozygotes f or a pathogenic variant sufficient to explain their disease. Although this varia nt has been reported in individuals with features of Marfan syndrome in the lite rature, this variant is likely benign based on its frequency in the general popu lation, lack of conservation, and the presence of other variants to explain dise ase in multiple individuals. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2021	Variant summary: FBN1 c.3509G>A (p.Arg1170His) results in a non-conservative amino acid change located in one of the EGF-like calcium-binding domains (IPR001881) 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 0.0014 in 396164 control chromosomes in the gnomAD database (version 2.1 and 3.1 datasets), including 1 homozygote. The observed variant frequency is approximately 12-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 benign. c.3509G>A has been reported in the literature in cohorts of individuals affected with Marfan Syndrome or Marfan-like syndrome (e.g. Hayward_1994, Montgomery_1998, Comeglio_2007, Robinson_2011, Howarth_2007, Waldmuller_2007, Volk_2014, Franken_2016), however, in some of these studies an incomplete Marfan phenotype was noted, or no exact phenotype information was provided. In a recent case-control study the variant was found in 11 cases of imaging supported nonsyndromic aortopathy and/or mitral valve disease, and in 14 carriers without cardiovascular disease, whereas only 12/101 (12%) of controls without pathogenic FBN1 variants (with sufficient imaging), had evidence of mitral valve or aortic disease in this study (Damrauer_2019). Co-occurrences with other pathogenic variants have been reported (FBN1 c.4913delA, p.Tyr1638fsX2 and FBN1 c.1633C>T, p.Arg545Cys, in internal LCA samples), providing supporting evidence for a benign role. Two publications reported that the variant had no effect on splicing examining blood RNA samples (Robinson_2011, Wai_2020), however these data do not allow any conclusion for the protein level effect of the variant. 15 other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 mostly without evidence for independent evaluation, and classified the variant as VUS (n=5), or likely benign (n=10). Based on the evidence outlined above, though the variant could be associated with an increased risk for nonsyndromic aortopathy and/or mitral valve disease, it was classified for the Marfan Syndrome phenotype as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 21, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

MASS syndrome

Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Dec 01, 1998

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

FBN1 NM_000138.4 exon 29 p.Arg1170His (c.3509G>A): This variant has been reported in at least four individuals with incomplete/suspected Marfan syndrome, segregating with suspected features in at least two different families (Hayward 1994 PMID:7870075, Montgomery 1998 PMID:9837823, Comeglio 2007 PMID:17657824, Stavropoulos 2016 PMID:28567303). Of note, these reported probands presented with primarily skeletal abnormalities; none fully met Ghent criteria for Marfan syndrome. Additionally, this variant did not segregate with disease in one family with suspected Marfan syndrome that was tested in our lab. This variant is present in 0.2% (286/129170) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-48779352-C-T) and is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:16451). This variant amino acid Histidine (His) is present in several bird species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Disproportionate tall stature

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Mar 25, 2014

- -

Acromicric dysplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Stiff skin syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Weill-Marchesani syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Geleophysic dysplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

FBN1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ectopia lentis 1, isolated, autosomal dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Ectopia lentis;C0024796:Marfan syndrome;C0265313:Weill-Marchesani syndrome;C0345050:Congenital aneurysm of ascending aorta;C1858556:MASS syndrome

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpretted as Likely benign and reported on 07/24/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Benign

-0.060

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.032

MetaRNN

Benign

0.049

MetaSVM

Uncertain

-0.053

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.50

Sift

Benign

0.21

Sift4G

Benign

0.17

Vest4

0.15

MVP

0.98

MPC

0.63

ClinPred

0.012

GERP RS

5.3

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over