rs767606368

chr15-48472673-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1 PP2 PP3 BP6_Strong BS2

The NM_000138.5(FBN1):c.4214T>G(p.Leu1405Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,614,024 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1405I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:10 B:8
• Conservation: PhyloP100: 4.63

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 -4 ACMG points.

• PM1: In a hotspot region, there are 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766
• BP6: Variant 15-48472673-A-C is Benign according to our data. Variant chr15-48472673-A-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 200041.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=9}. Variant chr15-48472673-A-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.4214T>G	p.Leu1405Arg	missense_variant	35/66	ENST00000316623.10
FBN1	NM_001406716.1	c.4214T>G	p.Leu1405Arg	missense_variant	34/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.4214T>G	p.Leu1405Arg	missense_variant	35/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251436 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135894

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000135 AC: 197 AN: 1461838 Hom.: 0 Cov.: 36 AF XY: 0.000129 AC XY: 94 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.000171

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

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: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000239 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces leucine with arginine at codon 1405 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with a connective tissue disease with vascular involvement (PMID: 19012347), recurrent spontaneous coronary dissections (PMID: 25519456), adolescent idiopathic scoliosis (PMID: 26333736), or arterial aneurysm and dissection (PMID: 32938213). This variant has been identified in 31/282836 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, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Dec 01, 2022	NM00138 c.4214T>G is a missense variant in FBN1 predicted to cause a substitution of leucine by an arginine at amino acid position 1405. This variant has been reported 14 times in ClinVar: 7 times as likely benign and 7 times as of uncertain significance (Variation ID: 200041). This variant has been reported in the literature and identified by multiple institutions in probands with various features of connective tissue but none with a diagnosis of Marfan syndrome (PMID: 19012347; Mayo Clinic, Bichat Hospital, Universitair Ziekenhuis Gent, Universitair Ziekenhuis Antwerpen). In one family, this variant was found to segregate with mitral valve dystrophy in one family member (Bichat Hospital). This variant has been identified in 0.021% (27/129150) of alleles in the European population in gnomAD v2.1.1 (BS1; https://gnomad.broadinstitute.org/variant/15-48764870-A-C). Computational prediction and evolutionary conservation anaylsis tools are unclear about this variant predicted impact (REVEL = 0.726 which is below 0.750 threshold). Due to there being insufficient evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 13, 2022	The p.L1405R variant (also known as c.4214T>G), located in coding exon 34 of the FBN1 gene, results from a T to G substitution at nucleotide position 4214. The leucine at codon 1405 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported in individuals with connective tissue disease (Rybczynski M et al. Am. J. Med. Genet. A, 2008 Dec;146A:3157-66) and adolescent idiopathic scoliosis (Haller G et al. J Bone Joint Surg Am, 2015 Sep;97:1411-7). This alteration was also describe to occur de novo in a case of spontaneous coronary artery dissection (von Hundelshausen P et al. Thromb. Haemost., 2015 Mar;113:668-70). None of the individuals met the diagnosis criteria for Marfan syndrome. In addition, one group also reported to detect this alteration in the in-house exome cases, including children without known vascular manifestations (von Hundelshausen P et al. Thromb. Haemost., 2015 Mar;113:668-70). This amino acid position is not 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 23, 2023	This missense variant replaces leucine with arginine at codon 1405 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with a connective tissue disease with vascular involvement (PMID: 19012347), recurrent spontaneous coronary dissections (PMID: 25519456), adolescent idiopathic scoliosis (PMID: 26333736), or arterial aneurysm and dissection (PMID: 32938213). This variant has been identified in 31/282836 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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 09, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2023	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: 24941995, 19012347, 26333736, 24833718, 25519456, 32938213, 12938084) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 27, 2017	The FBN1 c.4214T>G, p.Leu1405Arg variant was previously detected in a healthy adult tested at ARUP. It has been reported three times in the medical literature: in association with a connective tissue disorder with vascular involvement (Rybczynski et al., 2008), in association with adolescent idiopathic scoliosis (Buchan et al., 2014), and as a de novo variant in a patient with spontaneous coronary artery dissection (von Hundelshausen et al., 2015). However, this variant is found in the genome Aggregation Database with a general population frequency of 0.01% (30 out of 277,184 chromosomes), while ClinVar lists it as a variant of uncertain significance (ClinVar ID 200041). The majority of pathogenic missense mutations associated with Marfan syndrome involve alterations to conserved residues in critical EFG-like domains, and although this variant is located in one of these domains, it is not within the EGF consensus sequence defined in the Ghent criteria (Loeys 2010). Computational algorithms make conflicting predictions as to its effect on protein structure and function (SIFT: tolerated, Poly-Phen 2: benign, Mutation Taster: disease causing). Based on all available evidence, the c.4214T>G variant is likely to be benign. -

FBN1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2023

The FBN1 c.4214T>G variant is predicted to result in the amino acid substitution p.Leu1405Arg. This variant has been reported in a patient with connective tissue disease and vascular involvement (Rybczynski et al. 2008. PubMed ID: 19012347). It has also been reported as a variant of uncertain significance in a patient with idiopathic scoliosis who did not have a dilated aorta or a clinical diagnosis of Marfan syndrome (Haller et al. 2015. PubMed ID: 26333736) and as a presumed pathogenic, de novo variant in a patient with recurrent spontaneous coronary dissection without Marfan syndrome (von Hundelshausen et al. 2014. PubMed ID: 25519456). This variant has conflicting interpretations regarding it pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/200041/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 01, 2021

Variant summary: FBN1 c.4214T>G (p.Leu1405Arg) 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 0.00011 in 251436 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4214T>G has been reported in the literature in a small family with Adoloscent idiopathic scoliosis in two siblings, but no significant features of Marfan syndrome, where it demonstrated incomplete segregation (unaffected mother with the variant) with disease (Buchan_2014, Haller_2015), a patient diagnosed with other connective tissue diseases with vascular involvement, but not Marfan syndrome (Rybczynski_2008), as a reportedly de-novo variant in a patient presenting with recurrent coronary dissections who did not fulfill the Ghent nosology for Marfan syndrome (von Hundelshausen_2015), in a family member of a kindred where the molecular basis of disease was attributed to a different cause, namely, a pathogenic variant in the COL5A1 gene (Richer_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Marfan syndrome and/or an FBN1 associated Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -

Stiff skin syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Weill-Marchesani syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Geleophysic dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Acromicric dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2023

- -

Ectopia lentis 1, isolated, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Uncertain	0.13
Cadd	Uncertain	24
Dann	Benign	0.87
Eigen	Benign	-0.0081
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.29	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.63
Sift	Benign	0.24	T
Sift4G	Benign	0.23	T
Vest4		0.72
MVP		0.94
MPC		1.4
ClinPred		0.081	T
GERP RS		5.6

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: rs767606368; hg19: chr15-48764870;