rs1555398387

Positions:

• chr15-48485409-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.3677G>T is a missense variant in FBN1 predicted to cause a substitution of a glycine by valine at amino acid 1226 (p.Gly1226Val), in a cbEGF-like domain of the protein. This variant was found in a pediatric proband with ectopia lentis and severe annuloaortic ectasia, which is a highly specific phenotype for Marfan syndrome (MFS) (PMID 26796135; PP4). This variant has been reported twice in ClinVar: once as likely pathogenic and once as uncertain significance (Variation ID: 495598). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.912). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to 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: PM2_Sup, PP2, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA392324369/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 7.89

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• 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
FBN1	NM_000138.5	c.3677G>T	p.Gly1226Val	missense_variant	30/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3677G>T	p.Gly1226Val	missense_variant	29/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3677G>T	p.Gly1226Val	missense_variant	30/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 09, 2022

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1226 of the FBN1 protein (p.Gly1226Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 26796135). ClinVar contains an entry for this variant (Variation ID: 495598). 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. -

Marfan syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

May 23, 2024

The NM_00138 c.3677G>T is a missense variant in FBN1 predicted to cause a substitution of a glycine by valine at amino acid 1226 (p.Gly1226Val), in a cbEGF-like domain of the protein. This variant was found in a pediatric proband with ectopia lentis and severe annuloaortic ectasia, which is a highly specific phenotype for Marfan syndrome (MFS) (PMID 26796135; PP4). This variant has been reported twice in ClinVar: once as likely pathogenic and once as uncertain significance (Variation ID: 495598). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.912). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to 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: PM2_Sup, PP2, PP3, PP4. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 08, 2016

Variant summary: The FBN1 c.3677G>T (p.Gly1226Val) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant has been reported in one patient with early-onset Marfan syndrome (Maeda_2016) and is absent in 121388 control chromosomes. The variant of interest has not, to our knowledge, been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.99
MutPred		0.94		Gain of catalytic residue at G1226 (P = 0.0464);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		6.0

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: rs1555398387; hg19: chr15-48777606;