rs1303389437

Positions:

• chr15-48613069-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS4_Moderate PP2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.188A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 63 (p.Tyr63Cys). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (PMID 17657824) (PP4). This variant in FBN1 has been reported three times in ClinVar: 1 time as uncertain significance, 1 time as likely pathogenic, and 1 time as pathogenic (Variation ID: 547296). This variant has previously been reported in at least two apparently unrelated individuals with ectopia lentis (PMID 25053872, 28941062) and in an individual with a suspected or confimed diagnosis of Marfan syndrome (Centre for Human Genetics, Inc. ClinVar entry) (PS4_mod). This variant has been identified in 1/112420 (0.0004%) individuals of European non-Finnish origin (https://gnomad.broadinstitute.org/version 2.1.1). Computational prediction tools and conservation analysis are inconclusive data with regards to a possible impact on this variant protein function and structure (REVEL: 0.72). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to the conflicting 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: PS4_Mod, PP2, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA392448489/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 2.75

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 Uncertain_significance. Variant got 4 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.188A>G	p.Tyr63Cys	missense_variant	3/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.188A>G	p.Tyr63Cys	missense_variant	2/65		NP_001393645.1
FBN1	NM_001406717.1	c.188A>G	p.Tyr63Cys	missense_variant	3/9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.188A>G	p.Tyr63Cys	missense_variant	3/66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.188A>G		non_coding_transcript_exon_variant	3/67	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.188A>G		non_coding_transcript_exon_variant	3/31	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.188A>G		non_coding_transcript_exon_variant	3/68			ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249416 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135264

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:1 Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Dec 21, 2023	The NM_00138 c.188A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 63 (p.Tyr63Cys). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (PMID 17657824) (PP4). This variant in FBN1 has been reported three times in ClinVar: 1 time as uncertain significance, 1 time as likely pathogenic, and 1 time as pathogenic (Variation ID: 547296). This variant has previously been reported in at least two apparently unrelated individuals with ectopia lentis (PMID 25053872, 28941062) and in an individual with a suspected or confimed diagnosis of Marfan syndrome (Centre for Human Genetics, Inc. ClinVar entry) (PS4_mod). This variant has been identified in 1/112420 (0.0004%) individuals of European non-Finnish origin (https://gnomad.broadinstitute.org/version 2.1.1). Computational prediction tools and conservation analysis are inconclusive data with regards to a possible impact on this variant protein function and structure (REVEL: 0.72). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). Due to the conflicting 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: PS4_Mod, PP2, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2021

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 547296). This missense change has been observed in individuals with FBN1-related conditions (PMID: 17657824, 25053872, 28941062). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the FBN1 protein (p.Tyr63Cys). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 14, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein 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 (PMID: 12938084); 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: 28941062, 25053872, 17657824, 20564469, 12938084) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.19	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Vest4		0.92
MutPred		0.90		Gain of disorder (P = 0.0389);
MVP		0.99
MPC		1.3
ClinPred		0.97	D
GERP RS		4.0

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: rs1303389437; hg19: chr15-48905266;