chr15-48495155-G-A

Position:

• chr15-48495155-G-A

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.2645C>T​(p.Ala882Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 10.0

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 TB 4 (size 51) in uniprot entity FBN1_HUMAN there are 14 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, 0.991
• PP5: Variant 15-48495155-G-A is Pathogenic according to our data. Variant chr15-48495155-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48495155-G-A is described in Lovd as [Likely_pathogenic]. Variant chr15-48495155-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.2645C>T	p.Ala882Val	missense_variant	22/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.2645C>T	p.Ala882Val	missense_variant	21/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.2645C>T	p.Ala882Val	missense_variant	22/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Jan 10, 2022	ACMG criteria used to clasify this variant: PP3, PM1, PS4, PM2, PM5 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 09, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 10, 2020	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 05, 2024	The p.A882V pathogenic mutation (also known as c.2645C>T), located in coding exon 21 of the FBN1 gene, results from a C to T substitution at nucleotide position 2645. The alanine at codon 882 is replaced by valine, an amino acid with similar properties, and is located in the hybrid motif #02 domain. This mutation has been reported in several individuals with Marfan syndrome (Loeys B et al. Hum. Mutat. 2004;24:140-6; Comeglio P et al. Hum. Mutat. 2007;28:928), and was indicated to have occurred de novo in an individual with Marfan syndrome; however, there was no information provided regarding his clinical diagnosis, family history, or parental testing (Spits C et al. Fertil. Steril. 2006;86:310-20). This mutation was also identified in an individual with ectopia lentis, minor skeletal and skin involvement, and no cardiovascular findings (Comeglio P et al. Hum. Mutat. 2007;28:928) and has been detected in aortic aneurysm and dissection cohorts (Weerakkody R et al. Genet. Med. 2018;20(11):1414-1422; Overwater E et al. Hum. Mutat. 2018;39(9):1173-1192). This mutation co-segregated with disease in one family tested in our laboratory and was reported to segregate with disease in at least two additional families (Comeglio P et al. Hum. Mutat., 2007 Sep;28:928; Howarth R et al. Genet. Test., 2007;11:146-52). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, no assertion criteria provided	research	Centre for Genomic and Experimental Medicine, University of Edinburgh	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 30, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 22, 2022	This missense variant replaces alanine with valine at codon 882 of hybrid motif 2 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six unrelated individuals affected with Marfan syndrome (PMID: 15241795, 16756980, 17657824, 19839986), in three individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 28973303, 29543232, 29907982), and in another three individuals with Marfan syndrome-related features (PMID: 20564469, 25652356, 17627385). It has been shown that this variant segregates with Marfan syndrome in a family with four affected carriers (communication with an external laboratory, ClinVar SCV000739791.3). This variant has been described as de novo in one of the probands with Marfan syndrome, although parental testing information was not provided (PMID: 16756980). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Apr 07, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2022	Described as de novo in one of these probands, although no specific clinical or family history information was provided (Spits et al., 2006); 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; Although this variant does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which represents the majority of pathogenic missense changes associated with Marfan syndrome, it is located in the Hybrid 2 domain and several nearby missense variants in this domain (G880S, G880D, G884E) have been reported in association with Marfan syndrome in HGMD and in the UMD-FBN1 database (HGMD; Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 21895641, 20564469, 19161152, 17627385, 16756980, 19839986, 17657824, 28973303, 30341550, 29907982, 29543232, 32123317, 12938084, 15241795) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 06, 2019

The FBN1 c.2645C>T; p.Ala882Val variant (rs794728195) has been described in several individuals with Marfan syndrome or other FBN1-related disorders (Comeglio 2007, Howarth 2007, Loeys 2004, Weerakkody 2018). It is reported as pathogenic/likely pathogenic by multiple sources in ClinVar (Variation ID: 200001) and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at codon 882 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered likely pathogenic. REFERENCES Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. Howarth R et al. Application of dHPLC for mutation detection of the fibrillin-1 gene for the diagnosis of Marfan syndrome in a National Health Service Laboratory. Genet Test. 2007 Summer;11(2):146-52. Loeys B et al. Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum Mutat. 2004 Aug;24(2):140-6. Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422. -

Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 24, 2018

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. -

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 31, 2017

Variant summary: The FBN1 c.2645C>T (p.Ala882Val) variant involves the alteration of a highly conserved nucleotide that resides within one of the TB domains (InterPro). 4/4 in silico tools used predict a damaging outcome for this variant. This variant is absent from control dataset of gnomAD and several control cohorts reported in the literature (~246118 chrs tested), but was identified in multiple affected individuals presenting with classical MFS, isolated EL and incomplete MFS (Loeys_2004; Spits_2006; Comeglio_2006; Howarth_2007; Turner_2009; Hung_2009). The variant appears to segregate with the disease (Howarth_2007). In addition, one clinical lab cites the variant with classification of Likely Pathogenic. Taken together, this variant is 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

Nov 11, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 882 of the FBN1 protein (p.Ala882Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome or thoracic aortic aneurysm and dissection (PMID: 15241795, 16756980, 19161152, 19839986, 20564469, 28973303). ClinVar contains an entry for this variant (Variation ID: 200001). 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) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

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 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Vest4		0.81
MutPred		0.94		Loss of glycosylation at S885 (P = 0.3859);
MVP		0.94
MPC		1.4
ClinPred		0.99	D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs794728195; hg19: chr15-48787352; COSMIC: COSV57322094;