rs137854480

Positions:

• chr15-48537629-G-A
• chr15-48537629-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000138.5(FBN1):​c.718C>T​(p.Arg240Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/18 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 8.12

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a region_of_interest Interaction with MFAP4 (size 210) in uniprot entity FBN1_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) 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, 0.927
• PP5: Variant 15-48537629-G-A is Pathogenic according to our data. Variant chr15-48537629-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48537629-G-A is described in Lovd as [Pathogenic]. Variant chr15-48537629-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.718C>T	p.Arg240Cys	missense_variant	7/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.718C>T	p.Arg240Cys	missense_variant	6/65		NP_001393645.1
FBN1	NM_001406717.1	c.718C>T	p.Arg240Cys	missense_variant	7/9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.718C>T	p.Arg240Cys	missense_variant	7/66	1	NM_000138.5	ENSP00000325527	P1
FBN1	ENST00000559133.6	c.718C>T	p.Arg240Cys	missense_variant, NMD_transcript_variant	7/67	1		ENSP00000453958
FBN1	ENST00000674301.2	c.718C>T	p.Arg240Cys	missense_variant, NMD_transcript_variant	7/68			ENSP00000501333
FBN1	ENST00000537463.6	c.636+82C>T		intron_variant, NMD_transcript_variant		5		ENSP00000440294

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 01, 2017	FBN1:NM_000138.4:exon7 p.Arg240Cys (c.718C>T): This variant has been reported in >5 individuals with Marfan syndrome, features of Marfan syndrome or isolated ectopia lentis (Loeys 2001 PMID11700157, Comeglio 2002 PMID 12446365, Korkko 2002 PMID11826022, Ades 2004 15054843, Vanita 2007 18079676, Stheneur 2009 PMID 19293843). This variant segregated with isolated ectopia lentis in >10 family members from 2 different families (Ades 2004 PMID 15054843, Vanita 2007 PMID 18079676). This variant is absent from large population studies and has been reported by multiple laboratories as pathogenic in ClinVar (Variant ID:16461). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, this variant is predicted to affect a cysteine residue. Cysteine in the FBN1 gene is reported to have important functional relevance; variants that involve a cysteine residue are reported to be particularly significant (Dietz, PMID: 20301510). In summary, this variant is classified as pathogenic based on presence of affected individuals, segregation data, absence from controls, and predicted variant impact to the protein. -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	Nov 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Two alternative amino acid changes at the same position has been observed in gnomAD (v3) (highest allele count: 3 heterozygotes, 0 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times in ClinVar, and has also been reported in multiple patients with ectopia lentis and Marfan syndrome (PMID: 30838813, 34281902). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 17, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.718C>Tp.Arg240Cys in FBN1 gene has been reported previously in heterozygous state in multiple individuals with Marfan syndrome and Chen Z, et al., 2022, Gong B, et al., 2019. The R240C variant introduces a cysteine residue within the TGF-binding protein domain 1 of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein. Studies have shown that missense variants in the FBN1 gene that substitute or produce cysteine are associated with a higher risk for ectopia lentis than other missense variants Faivre L, et al., 2007. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Arginine at position 240 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Arg240Cys in FBN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 03, 2021	The p.R240C pathogenic mutation (also known as c.718C>T), located in coding exon 6 of the FBN1 gene, results from a C to T substitution at nucleotide position 718. The arginine at codon 240 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the hybrid module #01 domain. This alteration has been reported in association with classic Marfan syndrome (Loeys B et al. Arch Intern Med. 2001;161(20):2447-54; Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8; Stark VC. Genes (Basel). 2020 07;11(7)), and has been detected in multiple individuals with isolated ectopia lentis (Körkkö J et al. J Med Genet. 2002;39(1):34-41; Comeglio P et al. Br J Ophthalmol. 2002;86(12):1359-62; Biggin A et al. Hum Mutat. 2004;23(1):99; Aragon-Martin JA et al. Hum Mutat. 2010;31(8):E1622-31). In addition, this alteration has been reported to segregate with disease in multiple affected individuals with isolated ectopia lentis in one family (Edwards MJ. Am J Med Gen. 1994;53(1):65-71; Adès LC et al. Am J Med Genet A. 2004;126A(3):284-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2023

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; Introduces a cysteine residue within a TGF-binding protein domain (aka TB domain or 8-Cysteine domain) and is expected to disrupt disulfide bonding within this domain; other missense substitutions that affect cysteine residues within this TGF-binding protein domain have been reported in association with various FBN1-related phenotypes, including Marfan syndrome (HGMD); This variant is associated with the following publications: (PMID: 34818515, 20564469, 9399842, 15054843, 12446365, 11826022, 14695540, 19293843, 17627385, 17679947, 17657824, 30838813, 30675029, 32679894, 33087929, 31950671, 29357934, 17701892, 11700157, 18079676) -

Familial ectopia lentis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 03, 2022

Variant summary: FBN1 c.718C>T (p.Arg240Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251516 control chromosomes (gnomAD). c.718C>T has been reported in the literature in multiple individuals affected with Marfan syndrome, features of Marfan syndrome or isolated ectopia lentis (examples: Loeys_2001, Korkko_2002, Comeglio_2002, Ades_2004 and Aragon-Martin_2010). These data indicate that the variant is very likely to be associated with disease. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as 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

Jan 11, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 240 of the FBN1 protein (p.Arg240Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ectopia lentis and/or Marfan syndrome (PMID: 11700157, 11826022, 15054843, 17657824, 18079676, 19293843, 20564469). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16461). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Ectopia lentis 1, isolated, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 17, 2010

- -

Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.19	D
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.98
MutPred		0.78		Loss of disorder (P = 0.1435);
MVP		0.95
MPC		1.7
ClinPred		1.0	D
GERP RS		4.5

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: rs137854480; hg19: chr15-48829826;