15-48437069-C-T

Position:

chr15-48437069-C-T

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:12

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 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, 0.987

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/exons	MANE	Protein	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.6388G>A	p.Glu2130Lys	missense_variant	53/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1 linkuse as main transcript	c.6388G>A	p.Glu2130Lys	missense_variant	52/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.6388G>A	p.Glu2130Lys	missense_variant	53/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Marfan syndrome

Pathogenic:4

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	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS6, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 19, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 06, 2024	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. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 20, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2022	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) -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 20, 2021

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

FBN1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 27, 2023

For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 200191). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 17253931, 19293843, 19533785, 28098115; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). 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). -

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:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Nov 22, 2021

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. -

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

MutationTaster

Benign

1.0

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