15-48452676-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):c.5431G>A(p.Glu1811Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1811G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.84

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 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48452675-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1330727.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 15-48452676-C-T is Pathogenic according to our data. Variant chr15-48452676-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48452676-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.5431G>A	p.Glu1811Lys	missense_variant	45/66	ENST00000316623.10
FBN1	NM_001406716.1	c.5431G>A	p.Glu1811Lys	missense_variant	44/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.5431G>A	p.Glu1811Lys	missense_variant	45/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251182 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:1

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:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2017

The p.E1811K variant (also known as c.5431G>A), located in coding exon 44 of the FBN1 gene, results from a G to A substitution at nucleotide position 5431. The glutamic acid at codon 1811 is replaced by lysine, an amino acid with similar properties, and is located in the cbEGF-like #26 domain. This alteration has been reported in multiple individuals with Marfan syndrome (Comeglio P et al. Hum. Mutat., 2007 Sep;28:928; Howarth R et al. Genet. Test., 2007;11:146-52; Attanasio M et al. Clin. Genet., 2008 Jul;74:39-46; Lu C et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2013 Jun;30:301-4; Attanasio M et al. Eur J Med Genet, 2013 Jul;56:356-60). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 27, 2017

Variant summary: The FBN1 c.5431G>A (p.Glu1811Lys) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 3/4 in silico tools (SNPs&GO not captured due to low reliability index). It is located 9 nucleotides downstream from intron-exon boundary and 5/5 splice prediction tools predict no significant impact on the utilization of consensus splice site; however, one tool (Human Splicing Finder) predicts creation of a de novo splice donor site. ESE finder predicts that this variant may affect ESE site of SRp40. It is located in calcium binding EGF domain 26 (InterPro) of the protein where cysteine residues are known to be critical. Other missense variants in nearby residues (C1806S, D1808H, C1812R, C1812Y, C1818G, etc.) have been reported in patients with Marfan syndrome, Marfan-like syndrome and related disorders (ref. HGMD), supporting the functional importance of this region. This variant was found in 1/121594 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125). In literature, this variant is regarded as pathogenic variant and is reported in several patients (at least 8 unrelated patients) with Marfan syndrome. However, there are no cosegregation and functional studies. While one clinical lab classifies it as likely pathogenic, another classifies it as variant of unknown significance. Taken together, this variant is currently classified as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 30, 2020

Not observed at a significant frequency in large population cohorts (Lek et al., 2016) Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#200063; Landrum et al., 2016) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function This variant is associated with the following publications: (PMID: 23744319, 23684891, 31211624, 18435798, 17657824, 17627385, 25525159) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 05, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1811 of the FBN1 protein (p.Glu1811Lys). This variant is present in population databases (rs761857514, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 17627385, 17657824, 18435798, 23684891, 23744319, 31211624, 32679894). ClinVar contains an entry for this variant (Variation ID: 200063). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Vest4		0.98
MutPred		0.95		Gain of methylation at E1811 (P = 0.0025);
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs761857514; hg19: chr15-48744873;