rs1555394196

chr15-48421608-C-Gchr15-48421608-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000138.5(FBN1):c.7649G>C(p.Cys2550Ser) 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. 11/17 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2550Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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 15 ACMG points.

• PS1: Transcript NM_000138.5 (FBN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 626877
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr15-48421608-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 590852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 15-48421608-C-G is Pathogenic according to our data. Variant chr15-48421608-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519756.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.7649G>C	p.Cys2550Ser	missense_variant	62/66	ENST00000316623.10
FBN1	NM_001406716.1	c.7649G>C	p.Cys2550Ser	missense_variant	61/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.7649G>C	p.Cys2550Ser	missense_variant	62/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2017

The p.C2550S variant (also known as c.7649G>C), located in coding exon 61 of the FBN1 gene, results from a G to C substitution at nucleotide position 7649. The cysteine at codon 2550 is replaced by serine, an amino acid with dissimilar properties, and is located in the cb EGF-like #40 domain. Internal structural analysis indicates this alteration would lead to the loss of an important structural motif in the cbEGF-like domain, and 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; Jensen SA. Structure. 2009;17(5):759-68). In addition, an alteration at the same amino acid position, C2550Y, has been identified in an individual reported to have Marfan syndrome (Pees C et al. Clin Genet. 2014;86:552-7). 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. -

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	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Vest4		0.98
MutPred		1.0		Gain of phosphorylation at S2547 (P = 0.1897);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		6.0

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: rs1555394196; hg19: chr15-48713805;