15-48495513-C-T

Position:

• chr15-48495513-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.2495G>A​(p.Cys832Tyr) variant causes a missense change. 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. C832W) 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:5
• Conservation: PhyloP100: 6.12

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain EGF-like 13; calcium-binding (size 39) in uniprot entity FBN1_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) 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 chr15-48495512-A-C 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). 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, 0.996
• PP5: Variant 15-48495513-C-T is Pathogenic according to our data. Variant chr15-48495513-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48495513-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.2495G>A	p.Cys832Tyr	missense_variant	21/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.2495G>A	p.Cys832Tyr	missense_variant	20/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.2495G>A	p.Cys832Tyr	missense_variant	21/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 03, 2018	This c.2495G>A (p.Cys832Tyr) variant in the FBN1 gene has been reported in multiple unrelated individuals with Marfan syndrome (PMID: 10464652, 16222657, 17657824) and is extremely rare in the general population. Other reports have also observed different changes at the same amino acid in patients with Marfan syndrome (PMID: 19839986, 24793577). There is also strong functional data supporting pathogenesis (PMID: 10486319, 10464652). This c.2495G>A (p.Cys832Tyr) variant in the FBN1 gene is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 04, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP3+PM1_Strong+PP2+PS4+PP4 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2022

Affects a cysteine residue within a calcium-binding 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 calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); 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: 10464652, 19839986, 31447099, 12938084, 10486319, 16222657, 17657824, 31098894, 24199744, 29357934) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 29, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys832 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19839986, 27906200), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). 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: 42311). This missense change has been observed in individuals with Marfan syndrome (PMID: 10464652, 16222657, 17657824, 24199744, 29357934). 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 cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 832 of the FBN1 protein (p.Cys832Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.97
MutPred		1.0		Gain of phosphorylation at C832 (P = 0.0837);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		5.9

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

Other links and lift over

dbSNP: rs397515775; hg19: chr15-48787710;