rs397515847

Positions:

• chr15-48427603-A-G
• chr15-48427603-A-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.7168T>C​(p.Cys2390Arg) 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. C2390S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

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 TB 9 (size 53) in uniprot entity FBN1_HUMAN there are 19 pathogenic changes around while only 6 benign (76%) 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 chr15-48427603-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 690431.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, 0.994
• PP5: Variant 15-48427603-A-G is Pathogenic according to our data. Variant chr15-48427603-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48427603-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.7168T>C	p.Cys2390Arg	missense_variant	58/66	ENST00000316623.10
FBN1	NM_001406716.1	c.7168T>C	p.Cys2390Arg	missense_variant	57/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.7168T>C	p.Cys2390Arg	missense_variant	58/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 20, 2015

The p.Cys2390Arg variant in FBN1 has been identified by our laboratory in 1 adul t with Marfan syndrome and segregated with disease in 2 affected children. It wa s absent from large population studies. A different amino acid change at the sam e position (p.Cys2390Ser) has been reported in one individual with clinical feat ures of Marfan syndrome (Rand-Hendriksen 2007), suggesting that a change at this position may not be tolerated. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. While cysteine subsituti ons are a common finding in individuals with Marfan syndrome (Schrijver 1999), t his variant is not located within the conserved cystein residues of the EGF-like domain. In summary, although additional studies are required to fully establish its clinical significance, the p.Cys2390Arg variant is likely pathogenic. -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 31, 2018

Variant summary: FBN1 c.7168T>C (p.Cys2390Arg) results in a non-conservative amino acid change located in the TB domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant affects a Cysteine, which "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." This variant is not located within the conserved cystein residues of the EGF-like domain, however, cysteine subsitutions are a common finding in individuals with Marfan syndrome (Schrijver 1999) and are listed as one of the criteria for causal FBN1 mutation (Loeys_2010). The variant was absent in 245812 control chromosomes (gnomAD). The variant, c.7168T>C, has not been reported in the literature in individuals affected with Marfan Syndrome but it has been observed in three affected individuals (1 adult with Marfan syndrome and segregated with disease in 2 affected children) tested in another clinical lab. Another variant, c.7168T>A, which affects the same Cysteine, Cys2390Ser has been reported in an affected MFS pt (Rand-Hendrikson_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2019

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys2390 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17663468). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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). This variant has been observed in an individual affected with aortic dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 42421). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 2390 of the FBN1 protein (p.Cys2390Arg). 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	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Vest4		0.99
MutPred		0.94		Gain of MoRF binding (P = 0.04);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.4

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: rs397515847; hg19: chr15-48719800;