rs368650399

chr15-48470735-G-Achr15-48470735-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_000138.5(FBN1):c.4358C>T(p.Pro1453Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1453Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 3.10

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000138.5
• PP2: Missense variant where missense usually causes diseases, FBN1
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.4358C>T	p.Pro1453Leu	missense_variant	36/66	ENST00000316623.10
FBN1	NM_001406716.1	c.4358C>T	p.Pro1453Leu	missense_variant	35/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.4358C>T	p.Pro1453Leu	missense_variant	36/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 152024 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251238 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.0000536 AC XY: 39 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000629

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000724 AC: 11 AN: 152024 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74240

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2023	Identified in a patient with non-syndromic thoracic aortic aneurysm and dissection (TAAD) in published literature (Yang et al., 2022); Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: Yang2022[CaseReport]) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 21, 2018	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 24, 2022	This missense variant replaces proline with leucine at codon 1453 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/282622 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 02, 2023	The p.P1453L variant (also known as c.4358C>T), located in coding exon 35 of the FBN1 gene, results from a C to T substitution at nucleotide position 4358. The proline at codon 1453 is replaced by leucine, an amino acid with similar properties, and is located in the cbEGF-like #21 domain. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 08, 2021

Variant summary: FBN1 c.4358C>T (p.Pro1453Leu) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251238 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4358C>T in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Marfan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 01, 2023

This missense variant replaces proline with leucine at codon 1453 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/282622 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 04, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1453 of the FBN1 protein (p.Pro1453Leu). This variant is present in population databases (rs368650399, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 501654). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.44	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.42
Sift	Benign	0.23	T
Sift4G	Benign	0.29	T
Vest4		0.57
MVP		0.56
MPC		0.89
ClinPred		0.22	T
GERP RS		6.1

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: rs368650399; hg19: chr15-48762932;