15-48444546-C-T

Position:

• chr15-48444546-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP2 PP3 PM2_Supporting PM1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.6032G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2011 (p.Cys2011Tyr). This variant has been reported four times in ClinVar: once as pathogenic, twice as likely pathogenic, and once as uncertain significance (Variation ID: 263898). At least two probands with clinical features of Marfan syndrome carry the same variant (internal lab data, PS4_Sup). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). This variant affects a cysteine residue in a calcium binding EGF-like domain. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Other missense variants disrupting the Cysteine at this position, (i.e. p.Cys2011Arg and p.Cys2011Ser), have been reported in individuals with features of Marfan syndrome (PMID 29907982, 31163209). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.921, PP3). 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: PM1_Strong, PS4_Sup, PM2_Sup, PP2, PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA10587803/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 5.74

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_pathogenic. Variant got 7 ACMG points.

• PM1: 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
FBN1	NM_000138.5	c.6032G>A	p.Cys2011Tyr	missense_variant	49/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.6032G>A	p.Cys2011Tyr	missense_variant	48/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.6032G>A	p.Cys2011Tyr	missense_variant	49/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Feb 22, 2024

The NM_00138 c.6032G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2011 (p.Cys2011Tyr). This variant has been reported four times in ClinVar: once as pathogenic, twice as likely pathogenic, and once as uncertain significance (Variation ID: 263898). At least two probands with clinical features of Marfan syndrome carry the same variant (internal lab data, PS4_Sup). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). This variant affects a cysteine residue in a calcium binding EGF-like domain. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Other missense variants disrupting the Cysteine at this position, (i.e. p.Cys2011Arg and p.Cys2011Ser), have been reported in individuals with features of Marfan syndrome (PMID 29907982, 31163209). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.921, PP3). 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: PM1_Strong, PS4_Sup, PM2_Sup, PP2, PP3 -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2015

The p.C2011Y variant (also known as c.6032G>A), located in coding exon 48 of the FBN1 gene, results from a G to A substitution at nucleotide position 6032. The cysteine at codon 2011 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #30 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Internal structural analysis indicates that this alteration eliminates a structurally critical disulfide in the structurally sensitive cbEGF domain #30 (Ambry internal data). A likely pathogenic alteration, p.C2011R, has been described in the same codon (Overwater E et al. Hum. Mutat., 2018 Sep;39:1173-1192). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2024

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; 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: 12938084) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2022

This missense change has been observed in individual(s) with Marfan syndrome (external communication). ClinVar contains an entry for this variant (Variation ID: 263898). 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. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). This variant disrupts the p.Cys2011 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 29907982, 31163209; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2011 of the FBN1 protein (p.Cys2011Tyr). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 16, 2020

Variant summary: FBN1 c.6032G>A (p.Cys2011Tyr) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251146 control chromosomes (gnomAD). To our knowledge, no occurrence of c.6032G>A in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, missense mutations affecting or creating cysteine residues or located within the conserved resides of the EGF consensus sequence are listed among the criteria for a causal FBN1 mutation when identified as de-novo (with proven paternity) in the revised Ghent criteria for the diagnosis of Marfan and related conditions (Loeys, BL et al, 2010). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.96
MutPred		0.83		Loss of methylation at K2010 (P = 0.0143);
MVP		0.98
MPC		1.8
ClinPred		0.97	D
GERP RS		6.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs886038967; hg19: chr15-48736743;