15-48421651-C-T

Position:

• chr15-48421651-C-T

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.7606G>A​(p.Gly2536Arg) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• 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]

FBN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a domain EGF-like 44; calcium-binding (size 42) in uniprot entity FBN1_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) 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, 0.967
• PP5: Variant 15-48421651-C-T is Pathogenic according to our data. Variant chr15-48421651-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48421651-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.7606G>A	p.Gly2536Arg	missense_variant	62/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.7606G>A	p.Gly2536Arg	missense_variant	61/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.7606G>A	p.Gly2536Arg	missense_variant	62/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1, PP1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2006	- -
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:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 02, 2022	The p.G2536R pathogenic mutation (also known as c.7606G>A), located in coding exon 61 of the FBN1 gene, results from a G to A substitution at nucleotide position 7606. The glycine at codon 2536 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in subjects with features of Marfan syndrome and thoracic aortic aneurysm and dissection (TAAD) and has been reported as a de novo occurrence (Comeglio P et al. Hum. Mutat., 2001 Sep;18:251; Rommel K et al. Hum. Mutat., 2005 Dec;26:529-39; Robinson DO et al. Clin. Genet., 2012 Sep;82:223-31; Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6; Proost D et al. Hum. Mutat., 2015 Aug;36:808-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, RNA studies show this alteration has an aberrant impact on splicing (Robinson DO et al. Clin. Genet., 2012 Sep;82:223-31). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 12, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2018	p.Gly2536Arg (GGG>AGG): c.7606 G>A in exon 62 of the FBN1 gene (NM_000138.4)The G2536R mutation in the FBN1 gene has been reported in multiple individuals with Marfan syndrome (FBN1-UMD database). Subsequently, G2536R is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. Mutations in nearby residues (C2541F, C2535W) have been reported in association with Marfan syndrome , supporting the functional importance of this region of the protein. Furthermore, the G2536R mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, G2536R in the FBN1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 04, 2023	- -

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

Aug 05, 2016

Variant summary: The FBN1 c.7606G>A (p.Gly2536Arg) variant located in a Ca2+ binding domain causing a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured here due to low reliability) predicting a damaging outcome. The variant of interest was not found in controls (ExAC, 1000 Gs, or ESP). The variant of interest has been reported in multiple affected individuals with varying phenotypes: MFS, MFS-like, and TAAD. In addition, a functional study (Robinson_2012) indicates the variant alterates splicing producing a 32 deletion transcript (<2% total product). Multiple reputable databases/clinical laboratories.Furthermore, mutations in nearby residues (C2541F, C2535W) have been reported in association with Marfan syndrome. Therefore, the variant of interest has been 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 18, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2536 of the FBN1 protein (p.Gly2536Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FBN1-related conditions (PMID: 11524736, 16220557, 17657824, 24793577, 25907466, 26272055). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 42429). 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%. Studies have shown that this missense change results in altered splicing and introduces a premature termination codon (PMID: 21895641). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	35
DANN	Pathogenic	1.0
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.54	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.83
Sift	Benign	0.084	T
Sift4G	Benign	0.096	T
Vest4		0.98
MutPred		0.79		Loss of glycosylation at K2538 (P = 0.158);
MVP		0.96
MPC		1.6
ClinPred		0.99	D
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.70		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397515854; hg19: chr15-48713848; COSMIC: COSV57318182; COSMIC: COSV57318182;