15-48610808-C-T

Position:

• chr15-48610808-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.266G>A​(p.Cys89Tyr) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C89S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.38

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 domain EGF-like 1 (size 31) in uniprot entity FBN1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 chr15-48610808-C-G is described in Lovd as [Likely_pathogenic].
• 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). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. GenCC has associacion of the 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, 0.99
• PP5: Variant 15-48610808-C-T is Pathogenic according to our data. Variant chr15-48610808-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48610808-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	c.266G>A	p.Cys89Tyr	missense_variant	4/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.266G>A	p.Cys89Tyr	missense_variant	3/65		NP_001393645.1
FBN1	NM_001406717.1	c.266G>A	p.Cys89Tyr	missense_variant	4/9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.266G>A	p.Cys89Tyr	missense_variant	4/66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.266G>A		non_coding_transcript_exon_variant	4/67	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.266G>A		non_coding_transcript_exon_variant	4/31	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.266G>A		non_coding_transcript_exon_variant	4/68			ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 04, 2023	PS4, PM1, PM2, PM5, PP3, PP5 -
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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2016

The p.C89Y pathogenic mutation (also known as c.266G>A), located in coding exon 3 of the FBN1 gene, results from a G to A substitution at nucleotide position 266. The cysteine at codon 89 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #01 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Internal structural analysis has suggested that this alteration eliminates a structurally important disulfide motif within a cbEGF domain involved in oligomerization of FBN1. This alteration has been detected in several individuals diagnosed with Marfan syndrome (MFS) (Pilop C et al. Circulation. 2009;120(11):983-91). In one study, this alteration was described to occur likely de novo in an individual with classic MFS (Stheneur C et al. Eur J Hum Genet. 2009;17:1121-8). Based on the supporting evidence, p.C89Y is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2024

Reported in multiple unrelated individuals with Marfan syndrome or suspected Marfan syndrome (PMID: 17253931, 17663468, 19293843, 25907466); Not observed at significant frequency in large population cohorts (gnomAD); Affects a cysteine residue within an EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); 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: 19293843, 17663468, 19720936, 24941995, 25907466, 11700157, 24035709, 31825148, 31730815, 35058154, 17253931, 12938084) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2022

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: 200141). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 12938084, 17253931, 19293843, 19720936). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 89 of the FBN1 protein (p.Cys89Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.72	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Vest4		0.98
MutPred		0.92		Loss of disorder (P = 0.0557);
MVP		0.93
MPC		1.9
ClinPred		0.99	D
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs112660651; hg19: chr15-48903005;