chr15-48446811-A-G

Position:

• chr15-48446811-A-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.5683T>C​(p.Cys1895Arg) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.00

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 17 ACMG points.

• PM1: In a domain EGF-like 32; calcium-binding (size 38) in uniprot entity FBN1_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.993
• PP5: Variant 15-48446811-A-G is Pathogenic according to our data. Variant chr15-48446811-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 237100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48446811-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.5683T>C	p.Cys1895Arg	missense_variant	47/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.5683T>C	p.Cys1895Arg	missense_variant	46/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.5683T>C	p.Cys1895Arg	missense_variant	47/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

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

Apr 08, 2016

The p.C1895R variant (also known as c.5683T>C), located in coding exon 46 of the FBN1 gene, results from a T to C substitution at nucleotide position 5683. The cysteine at codon 1895 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like #28 domain. This variant was reported in a patient with Marfan syndrome (Arbustini E et al, Hum Mutat. 2005 Nov; 26(5):494), as well as another individual with features of connective tissue disorder (Oh MR et al, Pediatr Int. 2000 Oct; 42(5):488-91). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6494 samples (12988 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on internal structural analysis, this variant results in a loss of the C1895-C1905 disulfide bond and is anticipated to result in a significant decrease in structural stability (Downing AK et al, Cell. 1996 May; 85(4):597-605). 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2020

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with Marfan syndrome (PMID: 11059536, 16222657, 29357934). ClinVar contains an entry for this variant (Variation ID: 237100). This sequence change replaces cysteine with arginine at codon 1895 of the FBN1 protein (p.Cys1895Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		1.0
MutPred		0.89		Gain of disorder (P = 0.0242);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		6.2

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: rs878853686; hg19: chr15-48739008;