15-48537628-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM1PM5PP2PP3_ModerateBS2

The NM_000138.5(FBN1):c.719G>A(p.Arg240His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,030 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. R240C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

FBN1
NM_000138.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 7.91

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a region_of_interest Interaction with MFAP4 (size 210) in uniprot entity FBN1_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) in NM_000138.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-48537629-G-A is described in Lovd as [Pathogenic].

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, 0.843

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5 link	c.719G>A	p.Arg240His	missense_variant	Exon 7 of 66	ENST00000316623.10	NP_000129.3	P35555
FBN1	NM_001406716.1 link	c.719G>A	p.Arg240His	missense_variant	Exon 6 of 65		NP_001393645.1
FBN1	NM_001406717.1 link	c.719G>A	p.Arg240His	missense_variant	Exon 7 of 9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBN1	ENST00000316623.10 link	c.719G>A	p.Arg240His	missense_variant	Exon 7 of 66	1	NM_000138.5	ENSP00000325527.5	P35555
FBN1	ENST00000559133.6 link	n.719G>A		non_coding_transcript_exon_variant	Exon 7 of 67	1		ENSP00000453958.2	H0YND0
FBN1	ENST00000674301.2 link	n.719G>A		non_coding_transcript_exon_variant	Exon 7 of 68			ENSP00000501333.2	A0A6I8PL22
FBN1	ENST00000537463.6 link	n.636+83G>A		intron_variant	Intron 7 of 30	5		ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:3

Mar 10, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 240 of the FBN1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two siblings affected with Marfan syndrome, who also carried a pathogenic truncation c.3861delC in the same gene (PMID: 19059503). Their affected mother carried the truncation variant, and this missense variant was inherited from unaffected father. This variant has been identified in 1/245956 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. -

Oct 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R240H variant (also known as c.719G>A), located in coding exon 6 of the FBN1 gene, results from a G to A substitution at nucleotide position 719. The arginine at codon 240 is replaced by histidine, an amino acid with highly similar properties. In one study, p.R240H was identified in two probands in one family in conjunction with the c.3861delC pathogenic FBN1 mutation. In this family, p.R240H was inherited from the unaffected father, and c.3861delC was inherited from the affected mother; however, the probands appeared to have a more severe clinical phenotype than their mother (Van Dijk FS et al. Eur J Med Genet. 2009;52(1):1-5). This amino acid position is highly 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. -

Dec 14, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Marfan syndrome

Uncertain:2

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 240 of the FBN1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two siblings affected with Marfan syndrome, who also carried a pathogenic truncation c.3861delC in the same gene (PMID: 19059503). Their affected mother carried the truncation variant, and this missense variant was inherited from unaffected father. This variant has been identified in 1/245956 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. -

not provided

Uncertain:2

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FBN1: PM2, PP3, PP4 -

Dec 07, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in two siblings with Marfan syndrome who also harbor a frameshift variant on the opposite allele (in trans); the p.(R240H) variant was inherited from the unaffected father (PMID: 19059503); Not observed at significant frequency in large population cohorts (gnomAD); Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; 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: 27582083, 27437668, 31098894, 12938084, 34426522, 24941995, 19059503) -

not specified

Uncertain:1

Mar 25, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBN1 c.719G>A (p.Arg240His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251226 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.719G>A has been reported in the literature in a family with Marfan Syndrome (van Dijk_2009). In this report, the two affected probands carried both the c.719G>A variant (inherited from their unaffected father) as well as the c.3861delC (inherited from their affected mother). While this suggests the truncating variant to be the causitive variant in this family, the authors note the c.719G>A variant may have a potentially modifying effect, as evidence by the probands having a more severe clinical phenotype than their mother (van Dijk_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has 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;C4707243:Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 240 of the FBN1 protein (p.Arg240His). This variant is present in population databases (rs768744583, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Marfan syndrome. In at least one individual, this variant co-occurred with a pathogenic variant in the FBN1 gene. (PMID: 19059503; internal data). ClinVar contains an entry for this variant (Variation ID: 449122). Invitae Evidence 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 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

Oct 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

-0.082

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.86

REVEL

Pathogenic

0.72

Sift

Benign

0.37

Sift4G

Benign

0.32

Vest4

0.92

MVP

0.92

MPC

1.6

ClinPred

0.97

GERP RS

5.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over