rs397515859

chr15-48415632-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.7955G>A(p.Cys2652Tyr) 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. 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. C2652R) has been classified as 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:3
• Conservation: PhyloP100: 7.91

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 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 chr15-48415633-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 527194.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 15-48415632-C-T is Pathogenic according to our data. Variant chr15-48415632-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48415632-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.7955G>A	p.Cys2652Tyr	missense_variant	64/66	ENST00000316623.10
FBN1	NM_001406716.1	c.7955G>A	p.Cys2652Tyr	missense_variant	63/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.7955G>A	p.Cys2652Tyr	missense_variant	64/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 24, 2009	- -
Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PVS2, PP4 -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 30, 2018

The C2652Y likely pathogenic variant in the FBN1 gene has been reported in at least one proband with a familial connective tissue disorder; this individual was described as having cardiovascular manifestations including aortic dilation, skeletal system involvement, and myopia (Turner et al., 2009). In addition, C2652Y was found in an affected relative, and it was absent in a second, unaffected relative (Howarth et al, 2007). Moreover, C2652Y is not observed in large population cohorts (Lek et al., 2016).The C2652Y variant results in a non-conservative amino acid substitution, and in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, C2652Y 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).In summary, C2652Y in the FBN1 gene is interpreted as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		1.0
MutPred		1.0		Gain of phosphorylation at C2652 (P = 0.0716);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs397515859; hg19: chr15-48707829;