15-48489875-T-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP2BP5BS1

This summary comes from the ClinGen Evidence Repository: The NM_000138 c.3058A>G, is a missense variant in FBN1 predicted to cause a substitution of a Threonine by Alanine at amino acid 1020 (p.Thr1020Ala). This variant was found in 12 probands with variable phenotypes, mostly thoracic aortic aneurysm or a marfanoid habitus. One proband additionally presented ectopia lentis. Two of these probands carried two other pathogenic variants: a variant in FBN1 (BP2) and a variant in TGFBR1 (BP5). The variant in FBN1 has been reported ten times in ClinVar: 8 times as likely benign and two times as a variant of uncertain significance (Variation ID: 42325). The variant has been reported in the literature in multiple affected individuals including one individual with classical Marfan syndrome (PMID:11175294), one individual with incomplete Marfan syndrome (PMID:18435798), one patient with MASS syndrome (PMID:25944730), and an individual with bicuspid aortic valve and aortic root aneurysm (PMID:28387797). This variant has also been reported in 3 patients with Lujan-Fryns syndrome (PMID:19293843, PMID:28027854), including two brothers with marfanoid habitus, learning disabilities without cardiac defects (PMID:28027854). These brothers also share a variant in MECP2. Segregation analysis in one family showed that the variant was also present in four additional family members, none of which had aortic aneurysm, two had a marfanoid habitus This variant has been identified in 80 individuals of European-non-Finnish origin (MAF: 0.062%) in gnomad v2.1.1 (https://gnomad.broadinstitute.org/) (BS1). 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 likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA013721/MONDO:0007947/022

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:13

Conservation

PhyloP100: 1.49

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 Likely_benign. Variant got -6 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.

BS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.3058A>G	p.Thr1020Ala	missense_variant	Exon 25 of 66	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.3058A>G	p.Thr1020Ala	missense_variant	Exon 24 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 link	c.3058A>G	p.Thr1020Ala	missense_variant	Exon 25 of 66	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000411

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000454

AC:

114

AN:

251294

Hom.:

AF XY:

0.000442

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.000625

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000330

AC:

482

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000355

AC XY:

258

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000452

Gnomad4 FIN exome

AF:

0.000506

Gnomad4 NFE exome

AF:

0.000303

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.000335

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000508

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000461

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.000948

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Marfan syndrome

Uncertain:1Benign:4

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2022

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000138 c.3058A>G, is a missense variant in FBN1 predicted to cause a substitution of a Threonine by Alanine at amino acid 1020 (p.Thr1020Ala). This variant was found in 12 probands with variable phenotypes, mostly thoracic aortic aneurysm or a marfanoid habitus. One proband additionally presented ectopia lentis. Two of these probands carried two other pathogenic variants: a variant in FBN1 (BP2) and a variant in TGFBR1 (BP5). The variant in FBN1 has been reported ten times in ClinVar: 8 times as likely benign and two times as a variant of uncertain significance (Variation ID: 42325). The variant has been reported in the literature in multiple affected individuals including one individual with classical Marfan syndrome (PMID: 11175294), one individual with incomplete Marfan syndrome (PMID: 18435798), one patient with MASS syndrome (PMID: 25944730), and an individual with bicuspid aortic valve and aortic root aneurysm (PMID: 28387797). This variant has also been reported in 3 patients with Lujan-Fryns syndrome (PMID: 19293843, PMID: 28027854), including two brothers with marfanoid habitus, learning disabilities without cardiac defects (PMID: 28027854). These brothers also share a variant in MECP2. Segregation analysis in one family showed that the variant was also present in four additional family members, none of which had aortic aneurysm, two had a marfanoid habitus This variant has been identified in 80 individuals of European-non-Finnish origin (MAF: 0.062%) in gnomad v2.1.1 (https://gnomad.broadinstitute.org/) (BS1). 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 likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2, BP5. -

not provided

Uncertain:2Benign:2

Dec 08, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The T1020A variant of uncertain significance in the FBN1 gene has been reported previously in association with Marfan syndrome (both classic and incomplete presentations), MASS syndrome, and Lujan-Fryns syndrome (Tiecke et al., 2001; Attanasio et al., 2008; Wooderchak-Donahue et al., 2015; Stheneur et al., 2009; Groth et al., 2015). The T1020A variant has also been identified in an individual with bicuspid aortic valve and aortic root aneurysm, yet no additional manifestations of Marfan syndrome (Girdauskas et al., 2017). Giorgio et al. (2016) reported a consanguineous family in which both the T1020A variant, as well as a variant in the MECP2 gene, were identified in two brothers with intellectual disability and Marfanoid habitus; both variants were absent in a healthy third brother. While the MECP2 variant was inherited from the mother (who showed a skewed X-inactivation pattern), the T1020A variant was inherited from the unaffected father (Giorgio et al., 2016). T1020A was reported in an individual with sudden death and hypertrophic cardiomyopathy identified on autopsy; variants in several other cardiac genes were also found (Sanchez et al., 2016). Although T1020A has been identified in several unrelated individuals referred for Marfan/TAAD testing at GeneDx, observation in these individuals, for whom segregation data is lacking, is not sufficient to determine the absolute pathogenicity of this variant. The T1020A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, the T1020A variant does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene. 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). Finally, T1020A was observed in 79/126,548 (0.06%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Let et al., 2016). -

Jul 21, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FBN1: BP4, BS1 -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Jan 26, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 28, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Oct 18, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr1020Ala variant in FBN1 is classified as likely benign because it has been identified in 0.06% (80/129022) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org). It has also been reported in 2 individuals with Marfan syndrome (Tiecke 2001, Attanasio 2008), 1 individual with MASS phenotype (Wooderchak-Donahue, 2014), and in 2 individuals with Lujan-Fryns syndrome (Stheneur 2009, Giorgio 2017), one of whom inherited the FBN1 variant from his unaffected father and also carried a MECP2 variant. ACMG/AMP Criteria applied: BS1, BP4, BP5. -

Oct 27, 2015

Blueprint Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FBN1-related disorder

Benign:1

Feb 02, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.18

Eigen_PC

Benign

0.028

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.70

M_CAP

Benign

0.032

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.69

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.52

REVEL

Uncertain

0.39

Sift

Benign

0.042

Sift4G

Benign

0.20

Vest4

0.11

MVP

0.98

MPC

0.49

ClinPred

0.018

GERP RS

5.7

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