15-48434656-A-G

Position:

• chr15-48434656-A-G

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.6554T>C​(p.Ile2185Thr) variant causes a missense change. 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: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:2
• Conservation: PhyloP100: 6.35

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 domain EGF-like 37; calcium-binding (size 39) in uniprot entity FBN1_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) 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, 0.894
• PP5: Variant 15-48434656-A-G is Pathogenic according to our data. Variant chr15-48434656-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.6554T>C	p.Ile2185Thr	missense_variant	54/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6554T>C	p.Ile2185Thr	missense_variant	53/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6554T>C	p.Ile2185Thr	missense_variant	54/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1, PP4 -
Uncertain significance, flagged submission	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

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 10, 2023

This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 17657824, 21542060, 24161884, 31211626; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2185 of the FBN1 protein (p.Ile2185Thr). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 519696). 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. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, flagged submission

clinical testing

Ambry Genetics

Feb 01, 2016

The p.I2185T variant (also known as c.6554T>C), located in coding exon 53 of the FBN1 gene, results from a T to C substitution at nucleotide position 6554. The isoleucine at codon 2185 is replaced by threonine, an amino acid with similar properties. This variant was observed in a Marfan syndrome cohort in which patients were described to have fulfilled revised Ghent nosology; however, clinical details were not provided (Baetens M et al. Hum. Mutat. 2011;32(9):1053-62; Aalberts JJ et al. Gene. 2014;534(1):40-3). In another study, this variant was observed in a patient with minor involvement of the skeletal system and major involvement of the cardiovascular system indicating revised Ghent nosology for a diagnosis of Marfan syndrome was not fulfilled (Comeglio P et al. Hum. Mutat. 2007;28(9):928). 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 well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.27	D
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.62
Sift	Benign	0.34	T
Sift4G	Benign	0.33	T
Vest4		0.83
MutPred		0.85		Gain of disorder (P = 0.0188);
MVP		0.97
MPC		1.0
ClinPred		0.76	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: rs910656654; hg19: chr15-48726853;