NM_000138.5:c.5726T>C

Variant names:

• chr15-48446768-A-G
• rs794728333
• NM_000138.5:c.5726T>C

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.5726T>C​(p.Ile1909Thr) 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: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 9.26

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 17 ACMG points.

• PM1: In a disulfide_bond (size 14) in uniprot entity FBN1_HUMAN there are 6 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 the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.942
• PP5: Variant 15-48446768-A-G is Pathogenic according to our data. Variant chr15-48446768-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.5726T>C	p.Ile1909Thr	missense_variant	Exon 47 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.5726T>C	p.Ile1909Thr	missense_variant	Exon 46 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.5726T>C	p.Ile1909Thr	missense_variant	Exon 47 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:3 Uncertain:1

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PS1, PP4 -

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Jun 13, 2023

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM1, PM2, PP3, PP5 -

not provided Pathogenic:1

Oct 30, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The I1909T variant in the FBN1 gene has been reported previously in a seven year-old male meeting diagnostic criteria for Marfan syndrome (Loeys et al., 2001). Additionally, this variant was listed in a study validating the detection of mutations in individuals with Marfan and Loeys-Dietz syndrome by massive parallel sequencing (Baetens et al., 2011). This variant has been observed in one other individual referred for genetic testing of Marfan syndrome/TAAD at GeneDx. The I1909T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. Missense variants in nearby residues have been reported in association with Marfan syndrome (Stenson et al, 2014). However, while the I1909T variant is located in a calcium-binding EGF-like domain of the fibrillin-1 protein, it does not affect a Cysteine residue within this domain. Cysteine substitutions in calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, additional evidence is needed to determine whether this variant is pathogenic or a rare benign variant -

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

Dec 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 200189). 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. This variant disrupts the p.Ile1909 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19293843), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 11700157, 21542060, 33230159; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1909 of the FBN1 protein (p.Ile1909Thr). This variant is not present in population databases (gnomAD no frequency). -

Cardiovascular phenotype Pathogenic:1

Jan 09, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I1909T variant (also known as c.5726T>C), located in coding exon 46 of the FBN1 gene, results from a T to C substitution at nucleotide position 5726. The isoleucine at codon 1909 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in several individuals with Marfan syndrome (Loeys B et al. Arch. Intern. Med., 2001 Nov;161:2447-54; Baetens M et al. Hum. Mutat., 2011 Sep;32:1053-62; Ambry internal data). This amino acid position is not well conserved in available vertebrate species; however, all available vertebrate species have either isoleucine or the highly similar valine as the reference amino acid. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.20	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.058	T
Vest4		0.82
MutPred		0.92		Gain of disorder (P = 0.0179);
MVP		0.98
MPC		0.70
ClinPred		0.91	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: rs794728333; hg19: chr15-48738965; COSMIC: COSV57317729; COSMIC: COSV57317729;