rs794728336

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP2PP3PM2_SupportingPS4

This summary comes from the ClinGen Evidence Repository: The NM_000138 c.7577A>G variant is a missense variant in FBN1 predicted to cause a substitution of asparagine by serine at position 2526. This variant has been identified in the literature and public and private databases in one proband with a clinical diagnosis of Marfan syndrome and in seven probands with thoracic aortic aneurysm and dissection (TAAD) and/or other features suggestive of Marfan syndrome (PS4; PMID:17657824, Invitae and GeneDx internal data, ClinVar ID: 200198, UZA internal data). This variant lies in a critical calcium binding site within a calcium-binding EGF domain; however, since asparagine to serine substitutions in these positions might be tolerated (PMID:31227806) the PM1 criterion has not been used. This variant is not present in gnomAD v2.1.1 or v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (PP3; REVEL = 0.821). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM2_supporting, PP2, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA017256/MONDO:0007947/022

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN1
ENST00000316623.10 missense

Scores

7
7
3

Clinical Significance

Likely pathogenic reviewed by expert panel P:2U:3

Conservation

PhyloP100: 8.02
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FBN1NM_000138.5 linkuse as main transcriptc.7577A>G p.Asn2526Ser missense_variant 62/66 ENST00000316623.10 NP_000129.3
FBN1NM_001406716.1 linkuse as main transcriptc.7577A>G p.Asn2526Ser missense_variant 61/65 NP_001393645.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBN1ENST00000316623.10 linkuse as main transcriptc.7577A>G p.Asn2526Ser missense_variant 62/661 NM_000138.5 ENSP00000325527 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461334
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726878
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Marfan syndrome Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationClinGen FBN1 Variant Curation Expert Panel, ClinGenJun 15, 2023The NM_000138 c.7577A>G variant is a missense variant in FBN1 predicted to cause a substitution of asparagine by serine at position 2526. This variant has been identified in the literature and public and private databases in one proband with a clinical diagnosis of Marfan syndrome and in seven probands with thoracic aortic aneurysm and dissection (TAAD) and/or other features suggestive of Marfan syndrome (PS4; PMID: 17657824, Invitae and GeneDx internal data, ClinVar ID: 200198, UZA internal data). This variant lies in a critical calcium binding site within a calcium-binding EGF domain; however, since asparagine to serine substitutions in these positions might be tolerated (PMID: 31227806) the PM1 criterion has not been used. This variant is not present in gnomAD v2.1.1 or v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (PP3; REVEL = 0.821). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM2_supporting, PP2, PP3). -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 02, 2023This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2526 of the FBN1 protein (p.Asn2526Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of FBN1-related conditions (PMID: 17657824; Invitae). ClinVar contains an entry for this variant (Variation ID: 200198). 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) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 28, 2022Variant summary: FBN1 c.7577A>G (p.Asn2526Ser) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250380 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7577A>G has been reported in the literature in at-least one 45 year old individual with incomplete Marfan syndrome and minor skeletal involvement (example, Comeglio_2007). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 02, 2023The p.N2526S variant (also known as c.7577A>G), located in coding exon 61 of the FBN1 gene, results from an A to G substitution at nucleotide position 7577. The asparagine at codon 2526 is replaced by serine, an amino acid with highly similar properties, and is located in the cb EGF-like #40 domain. This alteration was detected in an adult patient reported to have some features of Marfan syndrome, but who did not meet diagnostic criteria (Comeglio P et al. Hum Mutat. 2007;28:928). This amino acid position is highly 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 provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 11, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17657824, 20591885) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
27
DANN
Uncertain
1.0
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Pathogenic
1.0
D
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-3.1
D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0060
D
Sift4G
Benign
0.074
T
Vest4
0.61
MutPred
0.85
Gain of disorder (P = 0.1413);
MVP
0.94
MPC
1.1
ClinPred
0.98
D
GERP RS
5.9

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs794728336; hg19: chr15-48713877; API