chr15-48437069-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000138.5(FBN1):c.6388G>A(p.Glu2130Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.91

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 Pathogenic. Variant got 17 ACMG points.

PM1

In a domain EGF-like 36; calcium-binding (size 38) in uniprot entity FBN1_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) in NM_000138.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.987

PP5

Variant 15-48437069-C-T is Pathogenic according to our data. Variant chr15-48437069-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48437069-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.6388G>A	p.Glu2130Lys	missense_variant	Exon 53 of 66	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.6388G>A	p.Glu2130Lys	missense_variant	Exon 52 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 link	c.6388G>A	p.Glu2130Lys	missense_variant	Exon 53 of 66	1	NM_000138.5	ENSP00000325527.5		P35555

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Marfan syndrome

Pathogenic:4

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PS6, PP4 -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant was co-segregated with Marfan syndrome in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 28098115, 29845260, 17253931, PP1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 28098115, 18435798, 17663468, 17253931, 19533785, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.974, 3CNET: 0.981, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:2

Apr 06, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E2130K pathogenic mutation (also known as c.6388G>A), located in coding exon 52 of the FBN1 gene, results from a G to A substitution at nucleotide position 6388. The glutamic acid at codon 2130 is replaced by lysine, an amino acid with similar properties and is located in the cbEGF-like #32 domain. This variant has been reported in individuals with Marfan syndrome (Tjeldhorn L et al. Genet Test, 2006;10:258-64; Rand-Hendriksen S et al. Am J Med Genet A, 2007 Sep;143A:1968-77; Attanasio M et al. Clin Genet, 2008 Jul;74:39-46; Chung BH et al. Am J Med Genet A, 2009 Jul;149A:1452-9; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Al-Haggar M et al. Saudi J Kidney Dis Transpl;28:141-148; Arnaud P et al. J Med Genet, 2017 02;54:100-103; Zhang M et al. Mol Med Rep, 2018 Jul;18:877-881; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637; Stark VC et al. Genes (Basel), 2020 Jul;11:[ePub ahead of print]; Duan DM et al. J Formos Med Assoc, 2022 Jun;121:1093-1101). This variant alters a conserved residue in the calcium-binding consensus sequence of a cbEGF domain and is expected to disrupt FBN1 function (Handford PA et al. Nature. 1991; 351(6322):164-7). In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Feb 19, 2020

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Aug 20, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBN1 c.6388G>A, p.Glu2130Lys variant has been reported in multiple individuals diagnosed with Marfan syndrome (Tjeldhorn 2006, Rand-Hendriksen 2007, Attanasio 2008, Stheneur 2009). It is listed in the ClinVar database (Variation ID: 200191), in the dbSNP variant database (rs794728334), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Exome Aggregation Consortium). The glutamine at residue 2130 is highly conserved, lies in the cbEGF domain, and any variation in the conserved residues of the consensus sequence is considered pathogenic (Loeys 2010). Additionally, computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. References: Attanasio M et al. FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Clin Genet. 2008 74(1):39-46. Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85. Rand-Hendriksen S et al. Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome. Am J Med Genet A. 2007 143A(17):1968-77. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 17(9):1121-8 Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006 10(4):258-64. -

Jun 10, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 200191; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17253931, 18435798, 19533785, 19293843, 17663468, 26684006, 31098894, 27234404, 20093880, 27382335, 27582083, 28098115, 30870686, 29845260, 32679894, 31825148) -

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

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Moderate+PP1+PP4+PP3_Strong+PP2 -

Nov 22, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FBN1 NM_000138.4 exon 53 p.Glu2130Lys (c.6388G>A): This variant has been reported in the literature in at least 5 individuals meeting Ghent criteria for Marfan syndrome (Tjeldhorn 2006 PMID:17253931, Rand-Hendriksen 2007 PMID:17663468, Attanasio 2008 PMID:18435798, Stheneur 2009 PMID:19293843, Al-Haggar 2017 PMID:28098115, Zhang 2018 PMID:29845260) and in one female with suspected Marfan syndrome who did not meet Ghent criteria (Chung 2009 PMID:19533785). This variant was also reported to segregate with disease in at least 3 affected family members (Al-Haggar 2017 PMID:28098115). This variant is not present in large control databases. It is present in ClinVar, with several labs classifying this variant as likely pathogenic or pathogenic (Variation ID:200191). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. -

See cases

Pathogenic:1

Dec 20, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS1,PM1,PM2,PP3,PP4 -

FBN1-related disorder

Pathogenic:1

May 26, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBN1 c.6388G>A variant is predicted to result in the amino acid substitution p.Glu2130Lys. This variant was reported in numerous individuals with Marfan syndrome, including at least one case confirmed to have occurred de novo (Tjeldhorn et al. 2006. PubMed ID: 17253931; Table S1, Li et al. 2019. PubMed ID: 31098894; Vanem et al. 2020. PubMed ID: 31825148; Zhao et al. 2020. PubMed ID: 32209317; Supplementary Data, Stark et al. 2020. PubMed ID: 32679894). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Nov 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2130 of the FBN1 protein (p.Glu2130Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 17253931, 19293843, 19533785, 28098115; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200191). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Vest4

0.92

MutPred

0.88

Gain of methylation at E2130 (P = 0.0074);

MVP

0.98

MPC

1.5

ClinPred

1.0

GERP RS

5.8

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